ID LRRK2_HUMAN Reviewed; 2527 AA. AC Q5S007; A6NJU2; Q6ZS50; Q8NCX9; DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 20-APR-2010, sequence version 2. DT 26-NOV-2014, entry version 117. DE RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2; DE EC=2.7.11.1; DE AltName: Full=Dardarin; GN Name=LRRK2; Synonyms=PARK8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND VARIANTS PARK8 RP VAL-1122; CYS-1441; CYS-1699 AND THR-2020. RC TISSUE=Brain; RX PubMed=15541309; DOI=10.1016/j.neuron.2004.11.005; RA Zimprich A., Biskup S., Leitner P., Lichtner P., Farrer M., RA Lincoln S.J., Kachergus J.M., Hulihan M.M., Uitti R.J., Calne D.B., RA Stoessl A.J., Pfeiffer R.F., Patenge N., Carballo Carbajal I., RA Vieregge P., Asmus F., Mueller-Myhsok B., Dickson D.W., Meitinger T., RA Strom T.M., Wszolek Z.K., Gasser T.; RT "Mutations in LRRK2 cause autosomal-dominant parkinsonism with RT pleomorphic pathology."; RL Neuron 44:601-607(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., RA Kucherlapati R., Weinstock G., Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2128-2527. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP DISEASE. RX PubMed=16081470; DOI=10.1093/brain/awh607; RA Adams J.R., van Netten H., Schulzer M., Mak E., McKenzie J., RA Strongosky A., Sossi V., Ruth T.J., Lee C.S., Farrer M., Gasser T., RA Uitti R.J., Calne D.B., Wszolek Z.K., Stoessl A.J.; RT "PET in LRRK2 mutations: comparison to sporadic Parkinson's disease RT and evidence for presymptomatic compensation."; RL Brain 128:2777-2785(2005). RN [5] RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT PARK8 THR-2020. RX PubMed=16321986; DOI=10.1093/hmg/ddi439; RA Gloeckner C.J., Kinkl N., Schumacher A., Braun R.J., O'Neill E., RA Meitinger T., Kolch W., Prokisch H., Ueffing M.; RT "The Parkinson disease causing LRRK2 mutation I2020T is associated RT with increased kinase activity."; RL Hum. Mol. Genet. 15:223-232(2006). RN [6] RP DISEASE. RX PubMed=16087219; DOI=10.1016/j.mad.2005.06.010; RA Toft M., Sando S.B., Melquist S., Ross O.A., White L.R., Aasly J.O., RA Farrer M.J.; RT "LRRK2 mutations are not common in Alzheimer's disease."; RL Mech. Ageing Dev. 126:1201-1205(2005). RN [7] RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS PARK8 CYS-1441 RP AND SER-2019. RX PubMed=16269541; DOI=10.1073/pnas.0507360102; RA West A.B., Moore D.J., Biskup S., Bugayenko A., Smith W.W., Ross C.A., RA Dawson V.L., Dawson T.M.; RT "Parkinson's disease-associated mutations in leucine-rich repeat RT kinase 2 augment kinase activity."; RL Proc. Natl. Acad. Sci. U.S.A. 102:16842-16847(2005). RN [8] RP SUBCELLULAR LOCATION, INTERACTION WITH PARK2, AND POSSIBLE FUNCTION. RX PubMed=16352719; DOI=10.1073/pnas.0508052102; RA Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., RA Dawson V.L., Dawson T.M., Ross C.A.; RT "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant RT LRRK2 induces neuronal degeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 102:18676-18681(2005). RN [9] RP TISSUE SPECIFICITY. RX PubMed=16532471; DOI=10.1002/ana.20808; RA Galter D., Westerlund M., Carmine A., Lindqvist E., Sydow O., RA Olson L.; RT "LRRK2 expression linked to dopamine-innervated areas."; RL Ann. Neurol. 59:714-719(2006). RN [10] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17120249; DOI=10.1002/ana.21019; RA Biskup S., Moore D.J., Celsi F., Higashi S., West A.B., Andrabi S.A., RA Kurkinen K., Yu S.W., Savitt J.M., Waldvogel H.J., Faull R.L., RA Emson P.C., Torp R., Ottersen O.P., Dawson T.M., Dawson V.L.; RT "Localization of LRRK2 to membranous and vesicular structures in RT mammalian brain."; RL Ann. Neurol. 60:557-569(2006). RN [11] RP FUNCTION, CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699; RP SER-2019 AND THR-2020, AND VARIANT MET-1906. RX PubMed=17114044; DOI=10.1016/j.neuron.2006.10.008; RA MacLeod D., Dowman J., Hammond R., Leete T., Inoue K., Abeliovich A.; RT "The familial Parkinsonism gene LRRK2 regulates neurite process RT morphology."; RL Neuron 52:587-593(2006). RN [12] RP FUNCTION. RX PubMed=20949042; DOI=10.1371/journal.pone.0013191; RA Zach S., Felk S., Gillardon F.; RT "Signal transduction protein array analysis links LRRK2 to Ste20 RT kinases and PKC zeta that modulate neuronal plasticity."; RL PLoS ONE 5:E13191-E13191(2010). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PRDX3, AND RP CHARACTERIZATION OF VARIANT PARK8 SER-2019. RX PubMed=21850687; DOI=10.1002/humu.21582; RA Angeles D.C., Gan B.H., Onstead L., Zhao Y., Lim K.L., Dachsel J., RA Melrose H., Farrer M., Wszolek Z.K., Dickson D.W., Tan E.K.; RT "Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 RT exacerbating oxidative stress-induced neuronal death."; RL Hum. Mutat. 32:1390-1397(2011). RN [14] RP FUNCTION, AND INTERACTION WITH TPCN2. RX PubMed=22012985; DOI=10.1093/hmg/ddr481; RA Gomez-Suaga P., Luzon-Toro B., Churamani D., Zhang L., Bloor-Young D., RA Patel S., Woodman P.G., Churchill G.C., Hilfiker S.; RT "Leucine-rich repeat kinase 2 regulates autophagy through a calcium- RT dependent pathway involving NAADP."; RL Hum. Mol. Genet. 21:511-525(2012). RN [15] RP SUBUNIT, AND AUTOPHOSPHORYLATION. RX PubMed=22952686; DOI=10.1371/journal.pone.0043472; RA Civiero L., Vancraenenbroeck R., Belluzzi E., Beilina A., RA Lobbestael E., Reyniers L., Gao F., Micetic I., De Maeyer M., RA Bubacco L., Baekelandt V., Cookson M.R., Greggio E., Taymans J.M.; RT "Biochemical characterization of highly purified leucine-rich repeat RT kinases 1 and 2 demonstrates formation of homodimers."; RL PLoS ONE 7:E43472-E43472(2012). RN [16] RP FUNCTION IN RETROGRADE TRANSPORT, INTERACTION WITH RAB29 AND VPS35, RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT PARK8 SER-2019, AND RP CHARACTERIZATION OF VARIANT MET-1906. RX PubMed=23395371; DOI=10.1016/j.neuron.2012.11.033; RA MacLeod D.A., Rhinn H., Kuwahara T., Zolin A., Di Paolo G., RA McCabe B.D., MacCabe B.D., Marder K.S., Honig L.S., Clark L.N., RA Small S.A., Abeliovich A.; RT "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting RT and Parkinson's disease risk."; RL Neuron 77:425-439(2013). RN [17] RP VARIANTS PARK8 GLY-1441 AND CYS-1699, AND TISSUE SPECIFICITY. RX PubMed=15541308; DOI=10.1016/j.neuron.2004.10.023; RA Paisan-Ruiz C., Jain S., Evans E.W., Gilks W.P., Simon J., RA van der Brug M., Lopez de Munain A., Aparicio S., Gil A.M., Khan N.L., RA Johnson J., Martinez J.R., Nicholl D., Carrera I.M., Pena A.S., RA de Silva R., Lees A.J., Marti-Masso J.F., Perez-Tur J., Wood N.W., RA Singleton A.B.; RT "Cloning of the gene containing mutations that cause PARK8-linked RT Parkinson's disease."; RL Neuron 44:595-600(2004). RN [18] RP VARIANT PARK8 SER-2019. RX PubMed=15726496; DOI=10.1086/429256; RA Kachergus J.M., Mata I.F., Hulihan M., Taylor J.P., Lincoln S., RA Aasly J.O., Gibson J.M., Ross O.A., Lynch T., Wiley J., Payami H., RA Nutt J., Maraganore D.M., Czyzewski K., Styczynska M., Wszolek Z.K., RA Farrer M.J., Toft M.; RT "Identification of a novel LRRK2 mutation linked to autosomal dominant RT parkinsonism: evidence of a common founder across European RT populations."; RL Am. J. Hum. Genet. 76:672-680(2005). RN [19] RP VARIANT PARK8 SER-2019. RX PubMed=15732108; DOI=10.1002/ana.20401; RA Hernandez D.G., Paisan-Ruiz C., McInerney-Leo A., Jain S., RA Meyer-Lindenberg A., Evans E.W., Berman K.F., Johnson J., Auburger G., RA Schaeffer A.A., Lopez G.J., Nussbaum R.L., Singleton A.B.; RT "Clinical and positron emission tomography of Parkinson's disease RT caused by LRRK2."; RL Ann. Neurol. 57:453-456(2005). RN [20] RP VARIANT PARK8/PD SER-2019. RX PubMed=15852371; DOI=10.1002/ana.20456; RA Aasly J.O., Toft M., Fernandez-Mata I., Kachergus J.M., Hulihan M., RA White L.R., Farrer M.J.; RT "Clinical features of LRRK2-associated Parkinson's disease in central RT Norway."; RL Ann. Neurol. 57:762-765(2005). RN [21] RP VARIANT PARK8 SER-2019. RX PubMed=16240353; DOI=10.1002/ana.20636; RG French Parkinson's disease genetics study group; RA Lesage S., Ibanez P., Lohmann E., Pollak P., Tison F., Tazir M., RA Leutenegger A.-L., Guimaraes J., Bonnet A.-M., Agid Y., Duerr A., RA Brice A.; RT "G2019S LRRK2 mutation in French and North African families with RT Parkinson's disease."; RL Ann. Neurol. 58:784-787(2005). RN [22] RP VARIANT PARK8 THR-2020. RX PubMed=15880653; DOI=10.1002/ana.20484; RA Funayama M., Hasegawa K., Ohta E., Kawashima N., Komiyama M., Kowa H., RA Tsuji S., Obata F.; RT "An LRRK2 mutation as a cause for the parkinsonism in the original RT PARK8 family."; RL Ann. Neurol. 57:918-921(2005). RN [23] RP VARIANT PARK8 SER-2019. RX PubMed=15929036; DOI=10.1002/ana.20510; RA Deng H., Le W., Guo Y., Hunter C.B., Xie W., Jankovic J.; RT "Genetic and clinical identification of Parkinson's disease patients RT with LRRK2 G2019S mutation."; RL Ann. Neurol. 57:933-934(2005). RN [24] RP VARIANTS PARK8 MET-793; ARG-930; CYS-1096 THR-1228; SER-2019 AND RP THR-2020, AND VARIANT LYS-551. RX PubMed=16251215; DOI=10.1093/brain/awh666; RA Berg D., Schweitzer K., Leitner P., Zimprich A., Lichtner P., RA Belcredi P., Bruessel T., Schulte C., Maass S., Naegele T.; RT "Type and frequency of mutations in the LRRK2 gene in familial and RT sporadic Parkinson's disease."; RL Brain 128:3000-3011(2005). RN [25] RP VARIANTS PARK8 CYS-1699; HIS-1941; SER-2019 AND ILE-2356. RX PubMed=16272164; DOI=10.1093/brain/awh667; RA Khan N.L., Jain S., Lynch J.M., Pavese N., Abou-Sleiman P.M., RA Holton J.L., Healy D.G., Gilks W.P., Sweeney M.G., Ganguly M., RA Gibbons V., Gandhi S., Vaughan J., Eunson L.H., Katzenschlager R., RA Gayton J., Lennox G., Revesz T., Nicholl D., Bhatia K.P., Quinn N., RA Brooks D., Lees A.J., Davis M.B., Piccini P., Singleton A.B., RA Wood N.W.; RT "Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial RT Parkinson's disease: clinical, pathological, olfactory and functional RT imaging and genetic data."; RL Brain 128:2786-2796(2005). RN [26] RP VARIANTS PARK8 VAL-1371; CYS-1441 AND SER-2019. RX PubMed=16333314; DOI=10.1038/sj.ejhg.5201539; RA Di Fonzo A., Tassorelli C., De Mari M., Chien H.F., Ferreira J., RA Rohe C.F., Riboldazzi G., Antonini A., Albani G., Mauro A., RA Marconi R., Abbruzzese G., Lopiano L., Fincati E., Guidi M., RA Marini P., Stocchi F., Onofrj M., Toni V., Tinazzi M., Fabbrini G., RA Lamberti P., Vanacore N., Meco G., Leitner P., Uitti R.J., RA Wszolek Z.K., Gasser T., Simons E.J., Breedveld G.J., Goldwurm S., RA Pezzoli G., Sampaio C., Barbosa E., Martignoni E., Oostra B.A., RA Bonifati V.; RT "Comprehensive analysis of the LRRK2 gene in sixty families with RT Parkinson's disease."; RL Eur. J. Hum. Genet. 14:322-331(2006). RN [27] RP VARIANT PARK8 SER-2019. RX PubMed=16272257; DOI=10.1136/jmg.2005.035568; RA Goldwurm S., Di Fonzo A., Simons E.J., Rohe C.F., Zini M., Canesi M., RA Tesei S., Zecchinelli A., Antonini A., Mariani C., Meucci N., RA Sacilotto G., Sironi F., Salani G., Ferreira J., Chien H.F., RA Fabrizio E., Vanacore N., Dalla Libera A., Stocchi F., Diroma C., RA Lamberti P., Sampaio C., Meco G., Barbosa E., Bertoli-Avella A.M., RA Breedveld G.J., Oostra B.A., Pezzoli G., Bonifati V.; RT "The G6055A (G2019S) mutation in LRRK2 is frequent in both early and RT late onset Parkinson's disease and originates from a common RT ancestor."; RL J. Med. Genet. 42:E65-E65(2005). RN [28] RP VARIANT PARK8 SER-2019. RX PubMed=15680455; DOI=10.1016/S0140-6736(05)17828-3; RG The Parkinson study group-PROGENI investigators; RA Nichols W.C., Pankratz N., Hernandez D., Paisan-Ruiz C., Jain S., RA Halter C.A., Michaels V.E., Reed T., Rudolph A., Shults C.W., RA Singleton A., Foroud T.; RT "Genetic screening for a single common LRRK2 mutation in familial RT Parkinson's disease."; RL Lancet 365:410-412(2005). RN [29] RP VARIANT PARK8 SER-2019. RX PubMed=15680456; DOI=10.1016/S0140-6736(05)17829-5; RG The Italian Parkinson genetics network; RA Di Fonzo A., Rohe C.F., Ferreira J., Chien H.F., Vacca L., Stocchi F., RA Guedes L., Fabrizio E., Manfredi M., Vanacore N., Goldwurm S., RA Breedveld G.J., Sampaio C., Meco G., Barbosa E., Oostra B.A., RA Bonifati V.; RT "A frequent LRRK2 gene mutation associated with autosomal dominant RT Parkinson's disease."; RL Lancet 365:412-415(2005). RN [30] RP VARIANT PARK8 SER-2019. RX PubMed=15680457; DOI=10.1016/S0140-6736(05)17830-1; RA Gilks W.P., Abou-Sleiman P.M., Gandhi S., Jain S., Singleton A., RA Lees A.J., Shaw K., Bhatia K.P., Bonifati V., Quinn N.P., Lynch J.M., RA Healy D.G., Holton J.L., Revesz T., Wood N.W.; RT "A common LRRK2 mutation in idiopathic Parkinson's disease."; RL Lancet 365:415-416(2005). RN [31] RP VARIANT PARK8 SER-2019. RX PubMed=15811454; DOI=10.1016/S0140-6736(05)74809-1; RA Toft M., Mata I.F., Kachergus J.M., Ross O.A., Farrer M.J.; RT "LRRK2 mutations and Parkinsonism."; RL Lancet 365:1229-1230(2005). RN [32] RP VARIANT SER-2019. RX PubMed=16001413; DOI=10.1002/mds.20618; RA Kay D.M., Kramer P., Higgins D.S., Zabetian C.P., Payami H.; RT "Escaping Parkinson's disease: a neurologically healthy octogenarian RT with the LRRK2 G2019S mutation."; RL Mov. Disord. 20:1077-1078(2005). RN [33] RP VARIANT PARK8 SER-2019. RX PubMed=16250030; DOI=10.1002/mds.20751; RA Kay D.M., Zabetian C.P., Factor S.A., Nutt J.G., Samii A., RA Griffith A., Bird T.D., Kramer P., Higgins D.S., Payami H.; RT "Parkinson's disease and LRRK2: frequency of a common mutation in U.S. RT movement disorder clinics."; RL Mov. Disord. 21:519-523(2006). RN [34] RP VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; GLN-1514; SER-1542; RP GLU-1598; CYS-1699; THR-1869; THR-2012; SER-2019; THR-2020 AND RP ARG-2385, AND VARIANTS PRO-119; LYS-551; VAL-723; MET-793; VAL-1122; RP ALA-1262; HIS-1398; PRO-1628; THR-1646; THR-1647; ASP-2081; LEU-2119; RP ILE-2261 AND THR-2397. RX PubMed=16172858; DOI=10.1007/s10048-005-0005-1; RA Mata I.F., Kachergus J.M., Taylor J.P., Lincoln S., Aasly J., RA Lynch T., Hulihan M.M., Cobb S.A., Wu R.-M., Lu C.-S., Lahoz C., RA Wszolek Z.K., Farrer M.J.; RT "Lrrk2 pathogenic substitutions in Parkinson's disease."; RL Neurogenetics 6:171-177(2005). RN [35] RP VARIANTS PARK8 VAL-1371 AND SER-2019, AND VARIANTS HIS-1398 AND RP THR-2397. RX PubMed=16157901; DOI=10.1212/01.WNL.0000167552.79769.b3; RA Paisan-Ruiz C., Lang A.E., Kawarai T., Sato C., Salehi-Rad S., RA Fisman G.K., Al-Khairallah T., St George-Hyslop P.H., Singleton A., RA Rogaeva E.; RT "LRRK2 gene in Parkinson disease: mutation analysis and case control RT association study."; RL Neurology 65:696-700(2005). RN [36] RP VARIANT PARK8 GLN-1067. RX PubMed=16247070; DOI=10.1212/01.wnl.0000180517.70572.37; RA Skipper L., Shen H., Chua E., Bonnard C., Kolatkar P., Tan L.C.S., RA Jamora R.D., Puvan K., Puong K.Y., Zhao Y., Pavanni R., Wong M.C., RA Yuen Y., Farrer M., Liu J.J., Tan E.K.; RT "Analysis of LRRK2 functional domains in nondominant Parkinson RT disease."; RL Neurology 65:1319-1321(2005). RN [37] RP VARIANTS PARK8 MET-793; THR-1869 AND SER-2019. RX PubMed=16157908; DOI=10.1212/01.WNL.0000169023.51764.b0; RA Farrer M., Stone J., Mata I.F., Lincoln S., Kachergus J., Hulihan M., RA Strain K.J., Maraganore D.M.; RT "LRRK2 mutations in Parkinson disease."; RL Neurology 65:738-740(2005). RN [38] RP VARIANTS PARK8 CYS-1441; HIS-1441 AND SER-2019. RX PubMed=16157909; DOI=10.1212/01.WNL.0000172630.22804.73; RA Zabetian C.P., Samii A., Mosley A.D., Roberts J.W., Leis B.C., RA Yearout D., Raskind W.H., Griffith A.; RT "A clinic-based study of the LRRK2 gene in Parkinson disease yields RT new mutations."; RL Neurology 65:741-744(2005). RN [39] RP VARIANT PARK8 GLY-1441. RX PubMed=15925109; DOI=10.1016/j.neulet.2005.03.033; RA Mata I.F., Taylor J.P., Kachergus J., Hulihan M., Huerta C., Lahoz C., RA Blazquez M., Guisasola L.M., Salvador C., Ribacoba R., Martinez C., RA Farrer M., Alvarez V.; RT "LRRK2 R1441G in Spanish patients with Parkinson's disease."; RL Neurosci. Lett. 382:309-311(2005). RN [40] RP VARIANT PARK8 SER-2019. RX PubMed=16298482; DOI=10.1016/j.neulet.2005.10.083; RA Infante J., Rodriguez E., Combarros O., Mateo I., Fontalba A., RA Pascual J., Oterino A., Polo J.M., Leno C., Berciano J.; RT "LRRK2 G2019S is a common mutation in Spanish patients with late-onset RT Parkinson's disease."; RL Neurosci. Lett. 395:224-226(2006). RN [41] RP VARIANT PARK8 SER-2019. RX PubMed=16102999; DOI=10.1016/j.parkreldis.2005.05.004; RA Gosal D., Ross O.A., Wiley J., Irvine G.B., Johnston J.A., Toft M., RA Mata I.F., Kachergus J., Hulihan M., Taylor J.P., Lincoln S.J., RA Farrer M.J., Lynch T., Mark Gibson J.; RT "Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a RT link between familial and idiopathic PD."; RL Parkinsonism Relat. Disord. 11:349-352(2005). RN [42] RP VARIANTS PARK8 CYS-1441; GLY-1441 AND SER-2019. RX PubMed=16533964; DOI=10.1001/archneur.63.3.377; RA Gaig C., Ezquerra M., Marti M.J., Munoz E., Valldeoriola F., RA Tolosa E.; RT "LRRK2 mutations in Spanish patients with Parkinson disease: RT frequency, clinical features, and incomplete penetrance."; RL Arch. Neurol. 63:377-382(2006). RN [43] RP CHARACTERIZATION OF VARIANT ARG-2385, AND ASSOCIATION WITH PARKINSON RP DISEASE. RX PubMed=17019612; DOI=10.1007/s00439-006-0268-0; RA Tan E.K., Zhao Y., Skipper L., Tan M.G., Di Fonzo A., Sun L., RA Fook-Chong S., Tang S., Chua E., Yuen Y., Tan L., Pavanni R., RA Wong M.C., Kolatkar P., Lu C.S., Bonifati V., Liu J.J.; RT "The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: RT genetic and functional evidence."; RL Hum. Genet. 120:857-863(2007). RN [44] RP VARIANTS [LARGE SCALE ANALYSIS] PRO-119; VAL-419; LYS-551; VAL-723; RP HIS-1398; GLN-1514; SER-1542; GLN-1550 AND PRO-1723. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [45] RP VARIANTS PARK8 VAL-712; LEU-1728; HIS-1728; SER-2019; MET-2141; RP HIS-2143 AND HIS-2466, AND VARIANTS SER-228; VAL-716; GLU-871; RP PHE-1870 AND LYS-2395. RX PubMed=18213618; DOI=10.1002/humu.20668; RA Paisan-Ruiz C., Nath P., Washecka N., Gibbs J.R., Singleton A.B.; RT "Comprehensive analysis of LRRK2 in publicly available Parkinson's RT disease cases and neurologically normal controls."; RL Hum. Mutat. 29:485-490(2008). RN [46] RP VARIANT ILE-1359. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., RA Davies H., Jones D., Lin M.L., Teague J., Bignell G., Butler A., RA Cho J., Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., RA Jia M., Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., RA Mudie L., Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., RA Kahnoski R.J., Anema J., Tuveson D.A., Perez-Mancera P.A., RA Mustonen V., Fischer A., Adams D.J., Rust A., Chan-On W., Subimerb C., RA Dykema K., Furge K., Campbell P.J., Teh B.T., Stratton M.R., RA Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex RT gene PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [47] RP ASSOCIATION OF VARIANTS PRO-1628 AND ARG-2385 WITH PARKINSON DISEASE. RX PubMed=21641266; DOI=10.1016/j.parkreldis.2010.11.008; RA Bardien S., Lesage S., Brice A., Carr J.; RT "Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) RT associated Parkinson's disease."; RL Parkinsonism Relat. Disord. 17:501-508(2011). RN [48] RP VARIANTS LYS-551; VAL-723; HIS-1398; GLN-1514; SER-1542; PRO-1628; RP THR-1646; THR-1647; ASP-2081 AND THR-2397. RX PubMed=22415848; DOI=10.1002/humu.22075; RA Rubio J.P., Topp S., Warren L., St Jean P.L., Wegmann D., Kessner D., RA Novembre J., Shen J., Fraser D., Aponte J., Nangle K., Cardon L.R., RA Ehm M.G., Chissoe S.L., Whittaker J.C., Nelson M.R., Mooser V.E.; RT "Deep sequencing of the LRRK2 gene in 14,002 individuals reveals RT evidence of purifying selection and independent origin of the RT p.Arg1628Pro mutation in Europe."; RL Hum. Mutat. 33:1087-1098(2012). RN [49] RP VARIANT PARK8 SER-2019. RX PubMed=22956510; DOI=10.1002/mds.25132; RA Kilarski L.L., Pearson J.P., Newsway V., Majounie E., Knipe M.D., RA Misbahuddin A., Chinnery P.F., Burn D.J., Clarke C.E., Marion M.H., RA Lewthwaite A.J., Nicholl D.J., Wood N.W., Morrison K.E., RA Williams-Gray C.H., Evans J.R., Sawcer S.J., Barker R.A., RA Wickremaratchi M.M., Ben-Shlomo Y., Williams N.M., Morris H.R.; RT "Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 RT (DJ-1) and LRRK2 in early-onset Parkinson's disease."; RL Mov. Disord. 27:1522-1529(2012). CC -!- FUNCTION: Positively regulates autophagy through a calcium- CC dependent activation of the CaMKK/AMPK signaling pathway. The CC process involves activation of nicotinic acid adenine dinucleotide CC phosphate (NAADP) receptors, increase in lysosomal pH, and calcium CC release from lysosomes. Together with RAB29, plays a role in the CC retrograde trafficking pathway for recycling proteins, such as CC mannose 6 phosphate receptor (M6PR), between lysosomes and the CC Golgi apparatus in a retromer-dependent manner. Regulates neuronal CC process morphology in the intact central nervous system (CNS). CC Phosphorylates PRDX3. May also have GTPase activity. May play a CC role in the phosphorylation of proteins central to Parkinson CC disease. {ECO:0000269|PubMed:17114044, CC ECO:0000269|PubMed:20949042, ECO:0000269|PubMed:21850687, CC ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23395371}. CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CC -!- SUBUNIT: Homodimer. Interacts with PARK2, PRDX3, RAB29, TPCN2 and CC VPS35. {ECO:0000269|PubMed:16352719, ECO:0000269|PubMed:21850687, CC ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:22952686, CC ECO:0000269|PubMed:23395371}. CC -!- INTERACTION: CC Self; NbExp=56; IntAct=EBI-5323863, EBI-5323863; CC Q9UKV8:AGO2; NbExp=3; IntAct=EBI-5323863, EBI-528269; CC P31749:AKT1; NbExp=6; IntAct=EBI-5323863, EBI-296087; CC Q8N6T3-2:ARFGAP1; NbExp=6; IntAct=EBI-5323863, EBI-6288865; CC Q62848:Arfgap1 (xeno); NbExp=7; IntAct=EBI-5323863, EBI-4398879; CC Q14155:ARHGEF7; NbExp=6; IntAct=EBI-5323863, EBI-717515; CC O95816:BAG2; NbExp=2; IntAct=EBI-5323863, EBI-355275; CC O95817:BAG3; NbExp=2; IntAct=EBI-5323863, EBI-747185; CC Q9UL15:BAG5; NbExp=12; IntAct=EBI-5323863, EBI-356517; CC Q16543:CDC37; NbExp=7; IntAct=EBI-5323863, EBI-295634; CC P60953:CDC42; NbExp=3; IntAct=EBI-5323863, EBI-81752; CC P05060:CHGB; NbExp=2; IntAct=EBI-5323863, EBI-712619; CC P30275:Ckmt1 (xeno); NbExp=2; IntAct=EBI-5323863, EBI-773103; CC P53355:DAPK1; NbExp=2; IntAct=EBI-5323863, EBI-358616; CC Q05193:DNM1; NbExp=4; IntAct=EBI-5323863, EBI-713135; CC P39053:Dnm1 (xeno); NbExp=3; IntAct=EBI-5323863, EBI-397785; CC O00429:DNM1L; NbExp=11; IntAct=EBI-5323863, EBI-724571; CC O00429-3:DNM1L; NbExp=2; IntAct=EBI-5323863, EBI-6896746; CC O14640-2:DVL1; NbExp=7; IntAct=EBI-5323863, EBI-6504027; CC O14641:DVL2; NbExp=3; IntAct=EBI-5323863, EBI-740850; CC Q92997:DVL3; NbExp=4; IntAct=EBI-5323863, EBI-739789; CC P30084:ECHS1; NbExp=2; IntAct=EBI-5323863, EBI-719602; CC Q13158:FADD; NbExp=4; IntAct=EBI-5323863, EBI-494804; CC O14976:GAK; NbExp=10; IntAct=EBI-5323863, EBI-714707; CC P49841:GSK3B; NbExp=7; IntAct=EBI-5323863, EBI-373586; CC P11142:HSPA8; NbExp=5; IntAct=EBI-5323863, EBI-351896; CC P07195:LDHB; NbExp=2; IntAct=EBI-5323863, EBI-358748; CC O75581:LRP6; NbExp=3; IntAct=EBI-5323863, EBI-910915; CC Q38SD2:LRRK1; NbExp=5; IntAct=EBI-5323863, EBI-1050422; CC P46821:MAP1B; NbExp=5; IntAct=EBI-5323863, EBI-9517186; CC P46734:MAP2K3; NbExp=5; IntAct=EBI-5323863, EBI-602462; CC P52564:MAP2K6; NbExp=4; IntAct=EBI-5323863, EBI-448135; CC O14733:MAP2K7; NbExp=3; IntAct=EBI-5323863, EBI-492605; CC P10636-2:MAPT; NbExp=3; IntAct=EBI-5323863, EBI-7796412; CC P10636-8:MAPT; NbExp=9; IntAct=EBI-5323863, EBI-366233; CC P42679:MATK; NbExp=2; IntAct=EBI-5323863, EBI-751664; CC P02687:MBP (xeno); NbExp=3; IntAct=EBI-5323863, EBI-908215; CC Q811U4:Mfn1 (xeno); NbExp=3; IntAct=EBI-5323863, EBI-9029118; CC O95140:MFN2; NbExp=3; IntAct=EBI-5323863, EBI-3324756; CC P26038:MSN; NbExp=15; IntAct=EBI-5323863, EBI-528768; CC Q96PY6:NEK1; NbExp=2; IntAct=EBI-5323863, EBI-373615; CC Q13469:NFATC2; NbExp=3; IntAct=EBI-5323863, EBI-716258; CC Q8WUM0:NUP133; NbExp=2; IntAct=EBI-5323863, EBI-295695; CC O60313:OPA1; NbExp=3; IntAct=EBI-5323863, EBI-1054131; CC Q9NQU5:PAK6; NbExp=2; IntAct=EBI-5323863, EBI-1053685; CC O60260:PARK2; NbExp=3; IntAct=EBI-5323863, EBI-716346; CC P00634:phoA (xeno); NbExp=2; IntAct=EBI-5323863, EBI-552958; CC P62136:PPP1CA; NbExp=6; IntAct=EBI-5323863, EBI-357253; CC P30048:PRDX3; NbExp=12; IntAct=EBI-5323863, EBI-748336; CC P17612:PRKACA; NbExp=6; IntAct=EBI-5323863, EBI-476586; CC P12369:Prkar2b (xeno); NbExp=3; IntAct=EBI-5323863, EBI-6096160; CC O14966:RAB29; NbExp=7; IntAct=EBI-5323863, EBI-372165; CC Q63481:Rab29 (xeno); NbExp=3; IntAct=EBI-5323863, EBI-6513837; CC P61020:RAB5B; NbExp=4; IntAct=EBI-5323863, EBI-399401; CC P61021:Rab5b (xeno); NbExp=2; IntAct=EBI-5323863, EBI-8320093; CC P63000:RAC1; NbExp=5; IntAct=EBI-5323863, EBI-413628; CC P41220:RGS2; NbExp=6; IntAct=EBI-5323863, EBI-712388; CC P62906:RPL10A; NbExp=2; IntAct=EBI-5323863, EBI-356860; CC P26373:RPL13; NbExp=2; IntAct=EBI-5323863, EBI-356849; CC P50914:RPL14; NbExp=2; IntAct=EBI-5323863, EBI-356746; CC P62750:RPL23A; NbExp=2; IntAct=EBI-5323863, EBI-353254; CC P62280:RPS11; NbExp=3; IntAct=EBI-5323863, EBI-1047710; CC P62841:RPS15; NbExp=8; IntAct=EBI-5323863, EBI-372635; CC P62249:RPS16; NbExp=2; IntAct=EBI-5323863, EBI-352480; CC P15880:RPS2; NbExp=2; IntAct=EBI-5323863, EBI-443446; CC P60866:RPS20; NbExp=2; IntAct=EBI-5323863, EBI-353105; CC P62266:RPS23; NbExp=2; IntAct=EBI-5323863, EBI-353072; CC P42677:RPS27; NbExp=2; IntAct=EBI-5323863, EBI-356336; CC P23396:RPS3; NbExp=2; IntAct=EBI-5323863, EBI-351193; CC Q99962:SH3GL2; NbExp=2; IntAct=EBI-5323863, EBI-77938; CC P12235:SLC25A4; NbExp=2; IntAct=EBI-5323863, EBI-359074; CC P05141:SLC25A5; NbExp=2; IntAct=EBI-5323863, EBI-355133; CC P12236:SLC25A6; NbExp=2; IntAct=EBI-5323863, EBI-356254; CC O95295:SNAPIN; NbExp=5; IntAct=EBI-5323863, EBI-296723; CC P37840:SNCA; NbExp=6; IntAct=EBI-5323863, EBI-985879; CC Q58A65:Spag9 (xeno); NbExp=2; IntAct=EBI-5323863, EBI-6530207; CC P07437:TUBB; NbExp=4; IntAct=EBI-5323863, EBI-350864; CC P04350:TUBB4A; NbExp=4; IntAct=EBI-5323863, EBI-355007; CC P31946:YWHAB; NbExp=5; IntAct=EBI-5323863, EBI-359815; CC P62258:YWHAE; NbExp=6; IntAct=EBI-5323863, EBI-356498; CC P61981:YWHAG; NbExp=4; IntAct=EBI-5323863, EBI-359832; CC P61983:Ywhag (xeno); NbExp=6; IntAct=EBI-5323863, EBI-359821; CC Q04917:YWHAH; NbExp=3; IntAct=EBI-5323863, EBI-306940; CC P27348:YWHAQ; NbExp=8; IntAct=EBI-5323863, EBI-359854; CC P63104:YWHAZ; NbExp=9; IntAct=EBI-5323863, EBI-347088; CC -!- SUBCELLULAR LOCATION: Membrane; Peripheral membrane protein. CC Cytoplasm. Perikaryon. Mitochondrion. Golgi apparatus. Cell CC projection, axon. Cell projection, dendrite. Endoplasmic reticulum CC {ECO:0000250}. Cytoplasmic vesicle {ECO:0000250}. Endosome CC {ECO:0000250}. Lysosome {ECO:0000250}. Mitochondrion outer CC membrane {ECO:0000250}. Mitochondrion inner membrane CC {ECO:0000250}. Mitochondrion matrix {ECO:0000250}. CC Note=Predominantly associated with intracytoplasmic vesicular and CC membranous structures (By similarity). Localized in the cytoplasm CC and associated with cellular membrane structures. Predominantly CC associated with the mitochondrial outer membrane of the CC mitochondria. Colocalized with RAB29 along tubular structures CC emerging from Golgi apparatus. Localizes in intracytoplasmic CC punctate structures of neuronal perikarya and dendritic and axonal CC processes. {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed in the brain. Expressed in pyramidal CC neurons in all cortical laminae of the visual cortex, in neurons CC of the substantia nigra pars compacta and caudate putamen (at CC protein level). Expressed throughout the adult brain, but at a CC lower level than in heart and liver. Also expressed in placenta, CC lung, skeletal muscle, kidney and pancreas. In the brain, CC expressed in the cerebellum, cerebral cortex, medulla, spinal cord CC occipital pole, frontal lobe, temporal lobe and putamen. CC Expression is particularly high in brain dopaminoceptive areas. CC {ECO:0000269|PubMed:15541308, ECO:0000269|PubMed:15541309, CC ECO:0000269|PubMed:16532471, ECO:0000269|PubMed:17120249}. CC -!- PTM: Autophosphorylated. CC -!- DISEASE: Parkinson disease 8 (PARK8) [MIM:607060]: A slowly CC progressive neurodegenerative disorder characterized by CC bradykinesia, rigidity, resting tremor, postural instability, CC neuronal loss in the substantia nigra, and the presence of CC neurofibrillary MAPT (tau)-positive and Lewy bodies in some CC patients. {ECO:0000269|PubMed:15541308, CC ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, CC ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, CC ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, CC ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, CC ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, CC ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, CC ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, CC ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, CC ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, CC ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, CC ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:16272257, CC ECO:0000269|PubMed:16298482, ECO:0000269|PubMed:16333314, CC ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:18213618, CC ECO:0000269|PubMed:22956510}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. {ECO:0000305}. CC -!- SIMILARITY: Contains 12 LRR (leucine-rich) repeats. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SIMILARITY: Contains 1 Roc domain. {ECO:0000255|PROSITE- CC ProRule:PRU00758}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY792511; AAV63975.1; -; mRNA. DR EMBL; AC079630; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC084290; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC107023; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL834529; CAD39185.1; -; mRNA. DR CCDS; CCDS31774.1; -. DR RefSeq; NP_940980.3; NM_198578.3. DR UniGene; Hs.187636; -. DR PDB; 2ZEJ; X-ray; 2.00 A; A/B=1333-1516. DR PDB; 3D6T; X-ray; 2.43 A; B=1335-1505. DR PDBsum; 2ZEJ; -. DR PDBsum; 3D6T; -. DR ProteinModelPortal; Q5S007; -. DR SMR; Q5S007; 1335-1512. DR BioGrid; 125700; 139. DR DIP; DIP-29684N; -. DR IntAct; Q5S007; 527. DR MINT; MINT-7997594; -. DR STRING; 9606.ENSP00000298910; -. DR BindingDB; Q5S007; -. DR ChEMBL; CHEMBL1075104; -. DR GuidetoPHARMACOLOGY; 2059; -. DR PhosphoSite; Q5S007; -. DR DMDM; 294862450; -. DR MaxQB; Q5S007; -. DR PaxDb; Q5S007; -. DR PRIDE; Q5S007; -. DR Ensembl; ENST00000298910; ENSP00000298910; ENSG00000188906. DR GeneID; 120892; -. DR KEGG; hsa:120892; -. DR UCSC; uc001rmg.4; human. DR CTD; 120892; -. DR GeneCards; GC12P040590; -. DR GeneReviews; LRRK2; -. DR HGNC; HGNC:18618; LRRK2. DR HPA; CAB037160; -. DR HPA; HPA014293; -. DR MIM; 168600; phenotype. DR MIM; 607060; phenotype. DR MIM; 609007; gene. DR neXtProt; NX_Q5S007; -. DR Orphanet; 2828; Young adult-onset Parkinsonism. DR PharmGKB; PA134968052; -. DR eggNOG; COG4886; -. DR GeneTree; ENSGT00530000063477; -. DR HOGENOM; HOG000293315; -. DR HOVERGEN; HBG081937; -. DR InParanoid; Q5S007; -. DR KO; K08844; -. DR OMA; FKIRDQP; -. DR PhylomeDB; Q5S007; -. DR TreeFam; TF313679; -. DR SignaLink; Q5S007; -. DR ChiTaRS; LRRK2; human. DR EvolutionaryTrace; Q5S007; -. DR GeneWiki; LRRK2; -. DR GenomeRNAi; 120892; -. DR NextBio; 80641; -. DR PRO; PR:Q5S007; -. DR Bgee; Q5S007; -. DR CleanEx; HS_LRRK2; -. DR ExpressionAtlas; Q5S007; baseline and differential. DR Genevestigator; Q5S007; -. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0032473; C:cytoplasmic side of mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0032839; C:dendrite cytoplasm; IDA:BHF-UCL. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0005768; C:endosome; ISS:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProt. DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProt. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0016234; C:inclusion body; IMP:ParkinsonsUK-UCL. DR GO; GO:0005764; C:lysosome; ISS:UniProtKB. DR GO; GO:0045121; C:membrane raft; IEA:Ensembl. DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:BHF-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:BHF-UCL. DR GO; GO:0043204; C:perikaryon; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0043195; C:terminal bouton; TAS:ParkinsonsUK-UCL. DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl. DR GO; GO:0003779; F:actin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0030276; F:clathrin binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0001948; F:glycoprotein binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. DR GO; GO:0034211; F:GTP-dependent protein kinase activity; IMP:UniProtKB. DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB. DR GO; GO:0003924; F:GTPase activity; IDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0044325; F:ion channel binding; IPI:UniProtKB. DR GO; GO:0016301; F:kinase activity; IDA:UniProtKB. DR GO; GO:0004708; F:MAP kinase kinase activity; IDA:BHF-UCL. DR GO; GO:0036479; F:peroxidase inhibitor activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0051018; F:protein kinase A binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0017048; F:Rho GTPase binding; IPI:BHF-UCL. DR GO; GO:0000149; F:SNARE binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0017075; F:syntaxin-1 binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0015631; F:tubulin binding; IDA:BHF-UCL. DR GO; GO:0000187; P:activation of MAPK activity; IDA:GOC. DR GO; GO:0000186; P:activation of MAPKK activity; IDA:BHF-UCL. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0034613; P:cellular protein localization; ISS:ParkinsonsUK-UCL. DR GO; GO:1903351; P:cellular response to dopamine; IMP:ParkinsonsUK-UCL. DR GO; GO:0071287; P:cellular response to manganese ion; IMP:ParkinsonsUK-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0008340; P:determination of adult lifespan; IMP:BHF-UCL. DR GO; GO:0006897; P:endocytosis; IMP:ParkinsonsUK-UCL. DR GO; GO:0035640; P:exploration behavior; IMP:BHF-UCL. DR GO; GO:0006184; P:GTP catabolic process; IDA:BHF-UCL. DR GO; GO:0048312; P:intracellular distribution of mitochondria; IMP:BHF-UCL. DR GO; GO:0035556; P:intracellular signal transduction; ISS:ParkinsonsUK-UCL. DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl. DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB. DR GO; GO:0034260; P:negative regulation of GTPase activity; IDA:MGI. DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; IMP:ParkinsonsUK-UCL. DR GO; GO:1902823; P:negative regulation of late endosome to lysosome transport; TAS:ParkinsonsUK-UCL. DR GO; GO:2000469; P:negative regulation of peroxidase activity; IDA:GOC. DR GO; GO:0032091; P:negative regulation of protein binding; IMP:ParkinsonsUK-UCL. DR GO; GO:0001933; P:negative regulation of protein phosphorylation; ISS:ParkinsonsUK-UCL. DR GO; GO:0010955; P:negative regulation of protein processing; IDA:ParkinsonsUK-UCL. DR GO; GO:1903217; P:negative regulation of protein processing involved in protein targeting to mitochondrion; IC:ParkinsonsUK-UCL. DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:1903125; P:negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0007528; P:neuromuscular junction development; IMP:BHF-UCL. DR GO; GO:0070997; P:neuron death; IMP:BHF-UCL. DR GO; GO:0048812; P:neuron projection morphogenesis; IMP:UniProtKB. DR GO; GO:0021772; P:olfactory bulb development; IMP:BHF-UCL. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL. DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:BHF-UCL. DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB. DR GO; GO:0060161; P:positive regulation of dopamine receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0043547; P:positive regulation of GTPase activity; IDA:GOC. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IC:ParkinsonsUK-UCL. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:BHF-UCL. DR GO; GO:1902499; P:positive regulation of protein autoubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0032092; P:positive regulation of protein binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:BHF-UCL. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IMP:ParkinsonsUK-UCL. DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:ParkinsonsUK-UCL. DR GO; GO:2000172; P:regulation of branching morphogenesis of a nerve; IMP:BHF-UCL. DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; IMP:BHF-UCL. DR GO; GO:0060159; P:regulation of dopamine receptor signaling pathway; ISS:ParkinsonsUK-UCL. DR GO; GO:0060079; P:regulation of excitatory postsynaptic membrane potential; ISS:ParkinsonsUK-UCL. DR GO; GO:0035564; P:regulation of kidney size; ISS:BHF-UCL. DR GO; GO:0040012; P:regulation of locomotion; IMP:BHF-UCL. DR GO; GO:0042391; P:regulation of membrane potential; IMP:BHF-UCL. DR GO; GO:0051900; P:regulation of mitochondrial depolarization; IMP:ParkinsonsUK-UCL. DR GO; GO:1902692; P:regulation of neuroblast proliferation; IMP:ParkinsonsUK-UCL. DR GO; GO:1901214; P:regulation of neuron death; IMP:ParkinsonsUK-UCL. DR GO; GO:0014041; P:regulation of neuron maturation; IMP:BHF-UCL. DR GO; GO:0010738; P:regulation of protein kinase A signaling; ISS:ParkinsonsUK-UCL. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; ISS:ParkinsonsUK-UCL. DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; IMP:ParkinsonsUK-UCL. DR GO; GO:1902803; P:regulation of synaptic vesicle transport; ISS:ParkinsonsUK-UCL. DR GO; GO:0006979; P:response to oxidative stress; IMP:BHF-UCL. DR GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:InterPro. DR GO; GO:0022028; P:tangential migration from the subventricular zone to the olfactory bulb; IMP:BHF-UCL. DR Gene3D; 1.25.10.10; -; 2. DR Gene3D; 1.25.40.20; -; 1. DR Gene3D; 2.130.10.10; -; 1. DR Gene3D; 3.40.50.300; -; 1. DR InterPro; IPR020683; Ankyrin_rpt-contain_dom. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR025875; Leu-rich_rpt_4. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR013684; MIRO-like. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR020859; ROC_GTPase. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR005225; Small_GTP-bd_dom. DR InterPro; IPR001806; Small_GTPase. DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom. DR InterPro; IPR001680; WD40_repeat. DR InterPro; IPR017986; WD40_repeat_dom. DR Pfam; PF00560; LRR_1; 1. DR Pfam; PF12799; LRR_4; 1. DR Pfam; PF13855; LRR_8; 1. DR Pfam; PF08477; Miro; 1. DR Pfam; PF00069; Pkinase; 1. DR PRINTS; PR00449; RASTRNSFRMNG. DR SMART; SM00369; LRR_TYP; 1. DR SMART; SM00320; WD40; 1. DR SUPFAM; SSF48371; SSF48371; 2. DR SUPFAM; SSF50978; SSF50978; 1. DR SUPFAM; SSF52540; SSF52540; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR TIGRFAMs; TIGR00231; small_GTP; 1. DR PROSITE; PS51450; LRR; 11. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS51424; ROC; 1. PE 1: Evidence at protein level; KW 3D-structure; ATP-binding; Autophagy; Cell projection; Coiled coil; KW Complete proteome; Cytoplasm; Cytoplasmic vesicle; Differentiation; KW Disease mutation; Endoplasmic reticulum; Endosome; Golgi apparatus; KW GTP-binding; GTPase activation; Kinase; Leucine-rich repeat; Lysosome; KW Membrane; Mitochondrion; Mitochondrion inner membrane; KW Mitochondrion outer membrane; Neurodegeneration; Nucleotide-binding; KW Parkinson disease; Parkinsonism; Phosphoprotein; Polymorphism; KW Reference proteome; Repeat; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1 2527 Leucine-rich repeat serine/threonine- FT protein kinase 2. FT /FTId=PRO_0000086238. FT REPEAT 983 1004 LRR 1. FT REPEAT 1012 1033 LRR 2. FT REPEAT 1036 1057 LRR 3. FT REPEAT 1059 1080 LRR 4. FT REPEAT 1084 1105 LRR 5. FT REPEAT 1108 1129 LRR 6. FT REPEAT 1130 1150 LRR 7. FT REPEAT 1174 1196 LRR 8. FT REPEAT 1197 1218 LRR 9. FT REPEAT 1221 1241 LRR 10. FT REPEAT 1246 1267 LRR 11. FT REPEAT 1269 1291 LRR 12. FT DOMAIN 1328 1511 Roc. {ECO:0000255|PROSITE- FT ProRule:PRU00758}. FT DOMAIN 1879 2138 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 1341 1348 GTP. {ECO:0000255|PROSITE- FT ProRule:PRU00758}. FT NP_BIND 1885 1893 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 2098 2121 GTP. {ECO:0000255|PROSITE- FT ProRule:PRU00758}. FT NP_BIND 2295 2298 GTP. {ECO:0000255|PROSITE- FT ProRule:PRU00758}. FT COILED 319 348 {ECO:0000255}. FT COMPBIAS 728 731 Poly-Leu. FT ACT_SITE 1994 1994 Proton acceptor. {ECO:0000255|PROSITE- FT ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10027}. FT BINDING 1906 1906 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT VARIANT 50 50 R -> H (in dbSNP:rs2256408). FT /FTId=VAR_024931. FT VARIANT 119 119 L -> P (in dbSNP:rs33995463). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846}. FT /FTId=VAR_024932. FT VARIANT 228 228 C -> S (in dbSNP:rs56108242). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054740. FT VARIANT 419 419 A -> V (in dbSNP:rs34594498). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_033903. FT VARIANT 551 551 N -> K (in dbSNP:rs7308720). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215, FT ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024933. FT VARIANT 712 712 M -> V (in PARK8). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054741. FT VARIANT 716 716 A -> V. {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054742. FT VARIANT 723 723 I -> V (in dbSNP:rs10878307). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024934. FT VARIANT 755 755 P -> L (in dbSNP:rs34410987). FT /FTId=VAR_033904. FT VARIANT 793 793 R -> M (in PARK8; unknown pathological FT significance; dbSNP:rs35173587). FT {ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215}. FT /FTId=VAR_024935. FT VARIANT 871 871 K -> E. {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054743. FT VARIANT 930 930 Q -> R (in PARK8; unknown pathological FT significance). FT {ECO:0000269|PubMed:16251215}. FT /FTId=VAR_024936. FT VARIANT 944 944 D -> Y (in dbSNP:rs17519916). FT /FTId=VAR_024937. FT VARIANT 1067 1067 R -> Q (in PARK8). FT {ECO:0000269|PubMed:16247070}. FT /FTId=VAR_024938. FT VARIANT 1096 1096 S -> C (in PARK8; unknown pathological FT significance). FT /FTId=VAR_024939. FT VARIANT 1122 1122 I -> V (in PARK8; dbSNP:rs34805604). FT {ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024940. FT VARIANT 1228 1228 S -> T (in PARK8). FT {ECO:0000269|PubMed:16251215}. FT /FTId=VAR_024941. FT VARIANT 1262 1262 P -> A (in dbSNP:rs4640000). FT {ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024942. FT VARIANT 1359 1359 K -> I (found in a renal cell carcinoma FT sample; somatic mutation). FT {ECO:0000269|PubMed:21248752}. FT /FTId=VAR_064728. FT VARIANT 1371 1371 I -> V (in PARK8; unknown pathological FT significance; dbSNP:rs17466213). FT {ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16333314}. FT /FTId=VAR_024943. FT VARIANT 1375 1375 D -> E (in dbSNP:rs28365226). FT /FTId=VAR_047022. FT VARIANT 1398 1398 R -> H (in dbSNP:rs7133914). FT {ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024944. FT VARIANT 1441 1441 R -> C (in PARK; shows an increase in FT activity in both autophosphorylation and FT phosphorylation of a generic substrate). FT {ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16333314, FT ECO:0000269|PubMed:16533964}. FT /FTId=VAR_024945. FT VARIANT 1441 1441 R -> G (in PARK8; shows a progressive FT reduction in neurite length and FT branching; dbSNP:rs33939927). FT {ECO:0000269|PubMed:15541308, FT ECO:0000269|PubMed:15925109, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16533964}. FT /FTId=VAR_024946. FT VARIANT 1441 1441 R -> H (in PARK8; pathogenicity has yet FT to be confirmed; dbSNP:rs34995376). FT {ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024947. FT VARIANT 1514 1514 R -> Q (in PARK8; pathogenicity has yet FT to be confirmed; might have an effect on FT protein structure; dbSNP:rs35507033). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024948. FT VARIANT 1542 1542 P -> S (in PARK8; pathogenicity has yet FT to be confirmed; might have an effect on FT protein structure; dbSNP:rs33958906). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024949. FT VARIANT 1550 1550 R -> Q (in an ovarian mucinous carcinoma FT sample; somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040678. FT VARIANT 1598 1598 V -> E (in PARK8; pathogenicity has yet FT to be confirmed; might have an effect on FT protein structure; dbSNP:rs721710). FT {ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024950. FT VARIANT 1628 1628 R -> P (may be associated with Parkinson FT disease in some populations; FT dbSNP:rs33949390). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024951. FT VARIANT 1646 1646 M -> T (in dbSNP:rs35303786). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024952. FT VARIANT 1647 1647 S -> T (in dbSNP:rs11564148). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024953. FT VARIANT 1699 1699 Y -> C (in PARK8; shows no progressive FT reduction in neurite length and FT branching; dbSNP:rs35801418). FT {ECO:0000269|PubMed:15541308, FT ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16272164}. FT /FTId=VAR_024954. FT VARIANT 1723 1723 R -> P (in an ovarian serous carcinoma FT sample; somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040679. FT VARIANT 1728 1728 R -> H (in PARK8). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054744. FT VARIANT 1728 1728 R -> L (in PARK8). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054745. FT VARIANT 1869 1869 M -> T (in PARK8; pathogenicity has yet FT to be confirmed; dbSNP:rs35602796). FT {ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024955. FT VARIANT 1870 1870 L -> F. {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054746. FT VARIANT 1906 1906 K -> M (does not inhibit interaction with FT RAB29; shows a progressive increase in FT neurite length and branching). FT {ECO:0000269|PubMed:17114044}. FT /FTId=VAR_071101. FT VARIANT 1941 1941 R -> H (in PARK8). FT {ECO:0000269|PubMed:16272164}. FT /FTId=VAR_024956. FT VARIANT 2012 2012 I -> T (in PARK8; pathogenicity FT uncertain; dbSNP:rs34015634). FT {ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024957. FT VARIANT 2019 2019 G -> S (in PARK8; shows an increase in FT activity in both autophosphorylation and FT phosphorylation of a generic substrate; FT results in increased PRDX3 FT phosphorylation promoting dysregulation FT of mitochondrial function and oxidative FT damage; does not inhibit interaction with FT RAB29; shows a progressive reduction in FT neurite length and branching; shows FT distinctive spheroid-like inclusions FT within both neuronal processes and at FT intracellular membranous structures; FT shows lysosomal swelling and reduced FT retrograde transport of selective cargo FT between lysosomes and the Golgi FT apparatus; shows apoptotic mechanism of FT cell death; dbSNP:rs34637584). FT {ECO:0000269|PubMed:15680455, FT ECO:0000269|PubMed:15680456, FT ECO:0000269|PubMed:15680457, FT ECO:0000269|PubMed:15726496, FT ECO:0000269|PubMed:15732108, FT ECO:0000269|PubMed:15811454, FT ECO:0000269|PubMed:15852371, FT ECO:0000269|PubMed:15929036, FT ECO:0000269|PubMed:16001413, FT ECO:0000269|PubMed:16102999, FT ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16157908, FT ECO:0000269|PubMed:16157909, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16240353, FT ECO:0000269|PubMed:16250030, FT ECO:0000269|PubMed:16251215, FT ECO:0000269|PubMed:16272164, FT ECO:0000269|PubMed:16272257, FT ECO:0000269|PubMed:16298482, FT ECO:0000269|PubMed:16333314, FT ECO:0000269|PubMed:16533964, FT ECO:0000269|PubMed:18213618, FT ECO:0000269|PubMed:22956510}. FT /FTId=VAR_024958. FT VARIANT 2020 2020 I -> T (in PARK8; significant increase in FT autophosphorylation of about 40% in FT comparison to wild-type protein in vitro; FT shows a progressive reduction in neurite FT length and branching; dbSNP:rs35870237). FT {ECO:0000269|PubMed:15541309, FT ECO:0000269|PubMed:15880653, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:16251215}. FT /FTId=VAR_024959. FT VARIANT 2081 2081 N -> D (in dbSNP:rs33995883). FT {ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024960. FT VARIANT 2119 2119 P -> L (in dbSNP:rs12423862). FT {ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024961. FT VARIANT 2141 2141 T -> M (in PARK8). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054747. FT VARIANT 2143 2143 R -> H (in PARK8). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054748. FT VARIANT 2261 2261 N -> I (in dbSNP:rs12581902). FT {ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024962. FT VARIANT 2356 2356 T -> I (in PARK8). FT {ECO:0000269|PubMed:16272164}. FT /FTId=VAR_024963. FT VARIANT 2385 2385 G -> R (associated with Parkinson FT disease; under conditions of oxidative FT stress the variant protein is more toxic FT and is associated with a higher rate of FT apoptosis; dbSNP:rs34778348). FT {ECO:0000269|PubMed:16172858}. FT /FTId=VAR_024964. FT VARIANT 2395 2395 E -> K. {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054749. FT VARIANT 2397 2397 M -> T (in dbSNP:rs3761863). FT {ECO:0000269|PubMed:16157901, FT ECO:0000269|PubMed:16172858, FT ECO:0000269|PubMed:22415848}. FT /FTId=VAR_024965. FT VARIANT 2466 2466 L -> H (in PARK8). FT {ECO:0000269|PubMed:18213618}. FT /FTId=VAR_054750. FT CONFLICT 212 212 L -> S (in Ref. 1; AAV63975). FT {ECO:0000305}. FT STRAND 1336 1341 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1347 1354 {ECO:0000244|PDB:2ZEJ}. FT STRAND 1370 1377 {ECO:0000244|PDB:2ZEJ}. FT STRAND 1389 1395 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1398 1402 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1406 1411 {ECO:0000244|PDB:2ZEJ}. FT STRAND 1412 1420 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1421 1423 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1425 1429 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1431 1441 {ECO:0000244|PDB:2ZEJ}. FT STRAND 1446 1452 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1454 1456 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1459 1472 {ECO:0000244|PDB:2ZEJ}. FT TURN 1473 1475 {ECO:0000244|PDB:2ZEJ}. FT STRAND 1481 1487 {ECO:0000244|PDB:2ZEJ}. FT HELIX 1495 1509 {ECO:0000244|PDB:2ZEJ}. SQ SEQUENCE 2527 AA; 286103 MW; 26142A0CECBBC3F4 CRC64; MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSER ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLIE VCPGTMQSLM GPQDVGNDWE VLGVHQLILK MLTVHNASVN LSVIGLKTLD LLLTSGKITL LILDEESDIF MLIFDAMHSF PANDEVQKLG CKALHVLFER VSEEQLTEFV ENKDYMILLS ALTNFKDEEE IVLHVLHCLH SLAIPCNNVE VLMSGNVRCY NIVVEAMKAF PMSERIQEVS CCLLHRLTLG NFFNILVLNE VHEFVVKAVQ QYPENAALQI SALSCLALLT ETIFLNQDLE EKNENQENDD EGEEDKLFWL EACYKALTWH RKNKHVQEAA CWALNNLLMY QNSLHEKIGD EDGHFPAHRE VMLSMLMHSS SKEVFQASAN ALSTLLEQNV NFRKILLSKG IHLNVLELMQ KHIHSPEVAE SGCKMLNHLF EGSNTSLDIM AAVVPKILTV MKRHETSLPV QLEALRAILH FIVPGMPEES REDTEFHHKL NMVKKQCFKN DIHKLVLAAL NRFIGNPGIQ KCGLKVISSI VHFPDALEML SLEGAMDSVL HTLQMYPDDQ EIQCLGLSLI GYLITKKNVF IGTGHLLAKI LVSSLYRFKD VAEIQTKGFQ TILAILKLSA SFSKLLVHHS FDLVIFHQMS SNIMEQKDQQ FLNLCCKCFA KVAMDDYLKN VMLERACDQN NSIMVECLLL LGADANQAKE GSSLICQVCE KESSPKLVEL LLNSGSREQD VRKALTISIG KGDSQIISLL LRRLALDVAN NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQS DDLDSEGSEG SFLVKKKSNS ISVGEFYRDA VLQRCSPNLQ RHSNSLGPIF DHEDLLKRKR KILSSDDSLR SSKLQSHMRH SDSISSLASE REYITSLDLS ANELRDIDAL SQKCCISVHL EHLEKLELHQ NALTSFPQQL CETLKSLTHL DLHSNKFTSF PSYLLKMSCI ANLDVSRNDI GPSVVLDPTV KCPTLKQFNL SYNQLSFVPE NLTDVVEKLE QLILEGNKIS GICSPLRLKE LKILNLSKNH ISSLSENFLE ACPKVESFSA RMNFLAAMPF LPPSMTILKL SQNKFSCIPE AILNLPHLRS LDMSSNDIQY LPGPAHWKSL NLRELLFSHN QISILDLSEK AYLWSRVEKL HLSHNKLKEI PPEIGCLENL TSLDVSYNLE LRSFPNEMGK LSKIWDLPLD ELHLNFDFKH IGCKAKDIIR FLQQRLKKAV PYNRMKLMIV GNTGSGKTTL LQQLMKTKKS DLGMQSATVG IDVKDWPIQI RDKRKRDLVL NVWDFAGREE FYSTHPHFMT QRALYLAVYD LSKGQAEVDA MKPWLFNIKA RASSSPVILV GTHLDVSDEK QRKACMSKIT KELLNKRGFP AIRDYHFVNA TEESDALAKL RKTIINESLN FKIRDQLVVG QLIPDCYVEL EKIILSERKN VPIEFPVIDR KRLLQLVREN QLQLDENELP HAVHFLNESG VLLHFQDPAL QLSDLYFVEP KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMSQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSEI IIRLYEMPYF PMGFWSRLIN RLLEISPYML SGRERALRPN RMYWRQGIYL NWSPEAYCLV GSEVLDNHPE SFLKITVPSC RKGCILLGQV VDHIDSLMEE WFPGLLEIDI CGEGETLLKK WALYSFNDGE EHQKILLDDL MKKAEEGDLL VNPDQPRLTI PISQIAPDLI LADLPRNIML NNDELEFEQA PEFLLGDGSF GSVYRAAYEG EEVAVKIFNK HTSLRLLRQE LVVLCHLHHP SLISLLAAGI RPRMLVMELA SKGSLDRLLQ QDKASLTRTL QHRIALHVAD GLRYLHSAMI IYRDLKPHNV LLFTLYPNAA IIAKIADYGI AQYCCRMGIK TSEGTPGFRA PEVARGNVIY NQQADVYSFG LLLYDILTTG GRIVEGLKFP NEFDELEIQG KLPDPVKEYG CAPWPMVEKL IKQCLKENPQ ERPTSAQVFD ILNSAELVCL TRRILLPKNV IVECMVATHH NSRNASIWLG CGHTDRGQLS FLDLNTEGYT SEEVADSRIL CLALVHLPVE KESWIVSGTQ SGTLLVINTE DGKKRHTLEK MTDSVTCLYC NSFSKQSKQK NFLLVGTADG KLAIFEDKTV KLKGAAPLKI LNIGNVSTPL MCLSESTNST ERNVMWGGCG TKIFSFSNDF TIQKLIETRT SQLFSYAAFS DSNIITVVVD TALYIAKQNS PVVEVWDKKT EKLCGLIDCV HFLREVMVKE NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEIQ SCLTVWDINL PHEVQNLEKH IEVRKELAEK MRRTSVE //