ID LRRK2_HUMAN Reviewed; 2527 AA. AC Q5S007; Q6ZS50; Q8NCX9; DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot. DT 21-DEC-2004, sequence version 1. DT 04-NOV-2008, entry version 44. 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 a large multifunctional protein (LRRK2) cause autosomal RT dominant parkinsonism with pleiomorphic a-synuclein and tau-pathology RT (PARK8)."; RL Neuron 44:601-607(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 402-1271. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2128-2527. RC TISSUE=Testis; RG The German cDNA consortium; RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases. 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 PD CYS-1441 AND RP 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 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 [11] RP VARIANT PARK8/PD 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 [12] 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 [13] 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 [14] 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 [15] 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 [16] RP VARIANT PD 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 [17] 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 [18] 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 [19] RP VARIANTS PD 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 [20] 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 [21] RP VARIANT PD 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 [22] 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 [23] RP VARIANT PD 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 [24] RP VARIANT PD 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 [25] 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 [26] RP VARIANT PD 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 [27] 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 [28] 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 [29] RP VARIANT PD 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 [30] RP VARIANTS PD 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 [31] RP VARIANTS PD 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 [32] RP VARIANT PD 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 [33] RP VARIANT PARK8/PD 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 [34] RP VARIANT PD 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 [35] RP VARIANTS PD 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 [36] 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). CC -!- FUNCTION: Probable protein kinase whose role is not yet known. May CC play a role in the phosphorylation of proteins central to CC Parkinson disease. May also have GTPase activity. CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CC -!- SUBUNIT: Interacts with PARK2. CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane CC protein. Note=Localized in the cytoplasm and associated with CC cellular membrane structures. Associates with the mitochondrial CC outer membrane. CC -!- TISSUE SPECIFICITY: 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 -!- DISEASE: Defects in LRRK2 are the cause of Parkinson disease 8 CC (PARK8) [MIM:607060, 168600]. Parkinson disease (PD) is a complex, CC multifactorial disorder that typically manifests after the age of CC 50 years, although early-onset cases (before 50 years) are known. CC PD generally arises as a sporadic condition but is occasionally CC inherited as a simple mendelian trait. Although sporadic and CC familial PD are very similar, inherited forms of the disease CC usually begin at earlier ages and are associated with atypical CC clinical features. PD is characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability, as well as by CC a clinically significant response to treatment with levodopa. The CC pathology involves the loss of dopaminergic neurons in the CC substantia nigra and the presence of Lewy bodies (intraneuronal CC accumulations of aggregated proteins), in surviving neurons in CC various areas of the brain. PARK8 is an autosomal-dominant late- CC onset parkinsonism, characterized by onset from 50 to 65 years, CC with slow progression and relatively benign course. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. CC -!- SIMILARITY: Contains 16 LRR (leucine-rich) repeats. CC -!- SIMILARITY: Contains 1 Miro domain. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.genetests.org/query?gene=LRRK2"; 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; AK127729; BAC87105.1; -; mRNA. DR EMBL; AL834529; CAD39185.1; -; mRNA. DR RefSeq; NP_940980.3; -. DR UniGene; Hs.187636; -. DR PDB; 2ZEJ; X-ray; 2.00 A; A/B=1338-1516. DR PDB; 3D6T; X-ray; 2.43 A; B=1335-1505. DR PDBsum; 2ZEJ; -. DR PDBsum; 3D6T; -. DR PhosphoSite; Q5S007; -. DR Ensembl; ENSG00000188906; Homo sapiens. DR GeneID; 120892; -. DR KEGG; hsa:120892; -. DR H-InvDB; HIX0010547; -. DR HGNC; HGNC:18618; LRRK2. DR HPA; HPA014293; -. DR MIM; 168600; phenotype. DR MIM; 607060; phenotype. DR MIM; 609007; gene. DR Orphanet; 2828; Parkinson disease, genetic types. DR PharmGKB; PA134968052; -. DR HOGENOM; Q5S007; -. DR HOVERGEN; Q5S007; -. DR NextBio; 80641; -. DR ArrayExpress; Q5S007; -. DR CleanEx; HS_LRRK2; -. DR GermOnline; ENSG00000188906; Homo sapiens. DR GO; GO:0032473; C:external side of mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0005624; C:membrane fraction; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IC:UniProtKB. DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB. DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0000165; P:MAPKKK cascade; IDA:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0046777; P:protein amino acid autophosphorylation; IDA:UniProtKB. DR InterPro; IPR011989; ARM-like. DR InterPro; IPR001611; LRR. DR InterPro; IPR013101; LRR_2. DR InterPro; IPR003591; LRR_sub-typ. DR InterPro; IPR013684; Miro-like. DR InterPro; IPR000719; Prot_kinase_core. DR InterPro; IPR017441; Protein_kinase_ATP_bd_CS. DR InterPro; IPR001806; Ras_trnsfrmng. DR InterPro; IPR017442; Se/Thr_pkinase-rel. DR InterPro; IPR008271; Ser_thr_pkin_AS. DR InterPro; IPR005225; Small_GTP_bd. DR InterPro; IPR015943; WD40/YVTN_repeat-like. DR InterPro; IPR001680; WD40_repeat. DR Gene3D; G3DSA:1.25.10.10; ARM-like; 1. DR Gene3D; G3DSA:2.130.10.10; WD40/YVTN_repeat-like; 1. DR Pfam; PF00560; LRR_1; 7. DR Pfam; PF07723; LRR_2; 1. DR Pfam; PF08477; Miro; 1. DR Pfam; PF00069; Pkinase; 1. DR PRINTS; PR00019; LEURICHRPT. DR PRINTS; PR00449; RASTRNSFRMNG. DR ProDom; PD000001; Prot_kinase; 2. DR SMART; SM00369; LRR_TYP; 1. DR SMART; SM00320; WD40; 1. DR TIGRFAMs; TIGR00231; small_GTP; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; ATP-binding; Coiled coil; Cytoplasm; Disease mutation; KW GTP-binding; GTPase activation; Kinase; Leucine-rich repeat; Membrane; KW Nucleotide-binding; Parkinson disease; Polymorphism; Repeat; KW Serine/threonine-protein kinase; Transferase. FT CHAIN 1 2527 Leucine-rich repeat serine/threonine- FT protein kinase 2. FT /FTId=PRO_0000086238. FT REPEAT 226 249 LRR 1. FT REPEAT 791 815 LRR 2. FT REPEAT 981 1004 LRR 3. FT REPEAT 1010 1033 LRR 4. FT REPEAT 1035 1057 LRR 5. FT REPEAT 1059 1081 LRR 6. FT REPEAT 1082 1105 LRR 7. FT REPEAT 1107 1127 LRR 8. FT REPEAT 1128 1151 LRR 9. FT REPEAT 1172 1194 LRR 10. FT REPEAT 1195 1219 LRR 11. FT REPEAT 1221 1243 LRR 12. FT REPEAT 1244 1268 LRR 13. FT REPEAT 1270 1291 LRR 14. FT DOMAIN 1335 1455 Miro. FT REPEAT 1556 1579 LRR 15. FT REPEAT 1861 1887 LRR 16. FT DOMAIN 1879 2138 Protein kinase. FT NP_BIND 1341 1348 GTP (Potential). FT NP_BIND 1885 1893 ATP (By similarity). FT NP_BIND 2098 2121 GTP (Potential). FT NP_BIND 2295 2298 GTP (Potential). FT COILED 319 348 Potential. FT COMPBIAS 728 731 Poly-Leu. FT ACT_SITE 1994 1994 Proton acceptor (By similarity). FT BINDING 1906 1906 ATP (By similarity). FT VARIANT 50 50 H -> R (in dbSNP:rs2256408). FT /FTId=VAR_024931. FT VARIANT 119 119 L -> P (in dbSNP:rs33995463). FT /FTId=VAR_024932. FT VARIANT 419 419 A -> V (in dbSNP:rs34594498). FT /FTId=VAR_033903. FT VARIANT 551 551 N -> K (in dbSNP:rs7308720). FT /FTId=VAR_024933. FT VARIANT 723 723 I -> V (in dbSNP:rs10878307). 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 and PD; idiopathic and FT late onset sporadic; could be a FT polymorphism; dbSNP:rs35173587). FT /FTId=VAR_024935. FT VARIANT 930 930 Q -> R (in PARK8; could be a FT poymorphism). FT /FTId=VAR_024936. FT VARIANT 944 944 D -> Y (in dbSNP:rs17519916). FT /FTId=VAR_024937. FT VARIANT 1067 1067 R -> Q (in PD; familial nondominant). FT /FTId=VAR_024938. FT VARIANT 1096 1096 S -> C (in PARK8; could be a FT polymorphism). FT /FTId=VAR_024939. FT VARIANT 1122 1122 I -> V (in PARK8; dbSNP:rs34805604). FT /FTId=VAR_024940. FT VARIANT 1228 1228 S -> T (in PARK8). FT /FTId=VAR_024941. FT VARIANT 1262 1262 P -> A (in dbSNP:rs4640000). FT /FTId=VAR_024942. FT VARIANT 1371 1371 I -> V (in PARK8 and PD; could be a FT polymorphism; dbSNP:rs17466213). 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 /FTId=VAR_024944. FT VARIANT 1441 1441 R -> C (in PARK8 and PD; autosomal FT dominant inheritance; show an increase in FT activity in both autophosphorylation and FT phosphorylation of a generic substrate; FT dbSNP:rs34995376). FT /FTId=VAR_024945. FT VARIANT 1441 1441 R -> G (in PARK8 and PD; sporadic late- FT onset patients). FT /FTId=VAR_024946. FT VARIANT 1441 1441 R -> H (in PARK8 and PD; sporadic; FT pathogenicity has yet to be confirmed). 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 /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 /FTId=VAR_024949. FT VARIANT 1550 1550 R -> Q (in an ovarian mucinous carcinoma FT sample; somatic mutation). 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 /FTId=VAR_024950. FT VARIANT 1628 1628 R -> P (in dbSNP:rs33949390). FT /FTId=VAR_024951. FT VARIANT 1646 1646 M -> T. FT /FTId=VAR_024952. FT VARIANT 1647 1647 S -> T (in dbSNP:rs11564148). FT /FTId=VAR_024953. FT VARIANT 1699 1699 Y -> C (in PARK8; dbSNP:rs35801418). FT /FTId=VAR_024954. FT VARIANT 1723 1723 R -> P (in an ovarian serous carcinoma FT sample; somatic mutation). FT /FTId=VAR_040679. FT VARIANT 1869 1869 M -> T (in PARK8 and PD; pathogenicity FT has yet to be confirmed). FT /FTId=VAR_024955. FT VARIANT 1941 1941 R -> H (in PARK8). FT /FTId=VAR_024956. FT VARIANT 2012 2012 I -> T (in PARK8; pathogenicity FT uncertain). FT /FTId=VAR_024957. FT VARIANT 2019 2019 G -> S (in PARK8 and PD; idiopathic or FT sporadic; the most common genetic FT determinant of PD identified so far; show FT an increase in activity in both FT autophosphorylation and phosphorylation FT of a generic substrate). 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 FT vitro). FT /FTId=VAR_024959. FT VARIANT 2081 2081 N -> D. FT /FTId=VAR_024960. FT VARIANT 2119 2119 P -> L (in dbSNP:rs12423862). FT /FTId=VAR_024961. FT VARIANT 2261 2261 N -> I (in dbSNP:rs12581902). FT /FTId=VAR_024962. FT VARIANT 2356 2356 T -> I (in PARK8). FT /FTId=VAR_024963. FT VARIANT 2385 2385 G -> R (in PARK8; pathogenicity has yet FT to be confirmed). FT /FTId=VAR_024964. FT VARIANT 2397 2397 M -> T (in dbSNP:rs3761863). FT /FTId=VAR_024965. FT CONFLICT 1260 1271 IPPEIGCLENLT -> VRRLLPLKKYTL (in Ref. 2). FT STRAND 1336 1341 FT HELIX 1347 1354 FT STRAND 1370 1377 FT STRAND 1389 1395 FT HELIX 1398 1402 FT HELIX 1406 1411 FT STRAND 1412 1420 FT HELIX 1421 1423 FT HELIX 1425 1429 FT HELIX 1431 1441 FT STRAND 1446 1452 FT HELIX 1454 1456 FT HELIX 1459 1472 FT TURN 1473 1475 FT STRAND 1481 1487 FT HELIX 1495 1509 SQ SEQUENCE 2527 AA; 286058 MW; 6F6070F2437B9C06 CRC64; MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLIE VCPGTMQSLM GPQDVGNDWE VLGVHQLILK MLTVHNASVN LSVIGLKTLD LLLTSGKITL LILDEESDIF MLIFDAMHSF PANDEVQKLG CKALHVLFER VSEEQLTEFV ENKDYMILLS ASTNFKDEEE 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 //