ID CLN5_HUMAN Reviewed; 358 AA. AC O75503; B3KQK7; DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot. DT 29-APR-2008, sequence version 2. DT 27-MAR-2024, entry version 185. DE RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5 {ECO:0000303|PubMed:37708259}; DE Short=BMP synthase CLN5; DE EC=2.3.1.- {ECO:0000269|PubMed:37708259}; DE AltName: Full=Ceroid-lipofuscinosis neuronal protein 5; DE Short=Protein CLN5; DE AltName: Full=Palmitoyl protein thioesterase CLN5; DE EC=3.1.2.22 {ECO:0000269|PubMed:35427157}; DE AltName: Full=S-depalmitoylase CLN5; DE Contains: DE RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5, secreted form; GN Name=CLN5; Synonyms=BMPS {ECO:0000303|PubMed:37708259}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT CLN5 ASN-230, VARIANT ARG-319, AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=9662406; DOI=10.1038/975; RA Savukoski M., Klockars T., Holmberg V., Santavuori P., Lander E.S., RA Peltonen L.; RT "CLN5, a novel gene encoding a putative transmembrane protein mutated in RT Finnish variant late infantile neuronal ceroid lipofuscinosis."; RL Nat. Genet. 19:286-288(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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 GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(2004). RN [4] RP SUBCELLULAR LOCATION, AND GLYCOSYLATION. RX PubMed=11971870; DOI=10.1093/hmg/11.8.885; RA Isosomppi J., Vesa J., Jalanko A., Peltonen L.; RT "Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 RT protein."; RL Hum. Mol. Genet. 11:885-891(2002). RN [5] RP FUNCTION (SECRETED FORM), INTERACTION WITH SORT1; RAB5A AND RAB7A, AND RP SUBCELLULAR LOCATION (SECRETED FORM). RX PubMed=22431521; DOI=10.1128/mcb.06726-11; RA Mamo A., Jules F., Dumaresq-Doiron K., Costantino S., Lefrancois S.; RT "The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal RT sorting."; RL Mol. Cell. Biol. 32:1855-1866(2012). RN [6] RP PROTEOLYTIC PROCESSING BY SPPL3, CLEAVAGE SITE, SUBCELLULAR LOCATION, AND RP TOPOLOGY. RX PubMed=28442266; DOI=10.1016/j.yexcr.2017.04.024; RA Jules F., Sauvageau E., Dumaresq-Doiron K., Mazzaferri J., Haug-Kroeper M., RA Fluhrer R., Costantino S., Lefrancois S.; RT "CLN5 is cleaved by members of the SPP/SPPL family to produce a mature RT soluble protein."; RL Exp. Cell Res. 357:40-50(2017). RN [7] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 1-358, CHARACTERIZATION OF RP VARIANTS CLN5 ASP-209 AND ASN-230, FUNCTION, CATALYTIC ACTIVITY, RP MUTAGENESIS OF VAL-101; ILE-115; HIS-117; CYS-231 AND ILE-259, RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, GLYCOSYLATION AT RP ASN-130; ASN-143; ASN-203 AND ASN-255, DISULFIDE BONDS, REACTION MECHANISM, RP AND ACTIVE SITE. RX PubMed=35427157; DOI=10.1126/sciadv.abj8633; RA Luebben A.V., Bender D., Becker S., Crowther L.M., Erven I., Hofmann K., RA Soeding J., Klemp H., Bellotti C., Staeuble A., Qiu T., Kathayat R.S., RA Dickinson B.C., Gaertner J., Sheldrick G.M., Kraetzner R., Steinfeld R.; RT "Cln5 represents a new type of cysteine-based S-depalmitoylase linked to RT neurodegeneration."; RL Sci. Adv. 8:eabj8633-eabj8633(2022). RN [8] RP VARIANT CLN5 HIS-63. RX PubMed=15728307; DOI=10.1212/01.wnl.0000151974.44980.f1; RA Pineda-Trujillo N., Cornejo W., Carrizosa J., Wheeler R.B., Munera S., RA Valencia A., Agudelo-Arango J., Cogollo A., Anderson G., Bedoya G., RA Mole S.E., Ruiz-Linares A.; RT "A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of RT juvenile onset."; RL Neurology 64:740-742(2005). RN [9] RP VARIANTS CLN5 PRO-63 AND ASN-230. RX PubMed=16814585; DOI=10.1016/j.ymgme.2006.04.010; RA Bessa C., Teixeira C.A., Mangas M., Dias A., Sa Miranda M.C., Guimaraes A., RA Ferreira J.C., Canas N., Cabral P., Ribeiro M.G.; RT "Two novel CLN5 mutations in a Portuguese patient with vLINCL: insights RT into molecular mechanisms of CLN5 deficiency."; RL Mol. Genet. Metab. 89:245-253(2006). RN [10] RP VARIANT CLN5 ASP-209. RX PubMed=17607606; DOI=10.1055/s-2007-981449; RA Cannelli N., Nardocci N., Cassandrini D., Morbin M., Aiello C., Bugiani M., RA Criscuolo L., Zara F., Striano P., Granata T., Bertini E., Simonati A., RA Santorelli F.M.; RT "Revelation of a novel CLN5 mutation in early juvenile neuronal ceroid RT lipofuscinosis."; RL Neuropediatrics 38:46-49(2007). RN [11] RP VARIANT CLN5 CYS-330, AND CHARACTERIZATION OF VARIANT CLN5 CYS-330. RX PubMed=19309691; DOI=10.1002/humu.21010; RA Lebrun A.-H., Storch S., Rueschendorf F., Schmiedt M.-L., Kyttaelae A., RA Mole S.E., Kitzmueller C., Saar K., Mewasingh L.D., Boda V., RA Kohlschuetter A., Ullrich K., Braulke T., Schulz A.; RT "Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes RT neuronal ceroid lipofuscinosis in Asian sibship."; RL Hum. Mutat. 30:E651-E661(2009). RN [12] RP CHARACTERIZATION OF VARIANTS CLN5 PRO-63; HIS-63 AND ASN-230, PROTEOLYTIC RP CLEAVAGE, SUBCELLULAR LOCATION (SECRETED FORM), AND GLYCOSYLATION. RX PubMed=20052765; DOI=10.1002/humu.21195; RA Schmiedt M.L., Bessa C., Heine C., Ribeiro M.G., Jalanko A., Kyttaelae A.; RT "The neuronal ceroid lipofuscinosis protein CLN5: new insights into RT cellular maturation, transport, and consequences of mutations."; RL Hum. Mutat. 31:356-365(2010). RN [13] RP VARIANTS CLN5 HIS-63; TYR-77; SER-143; PRO-149; SER-156; ARG-158; SER-158; RP ASP-209 AND CYS-325, AND VARIANTS ARG-26 AND LYS-193. RX PubMed=21990111; DOI=10.1002/humu.21624; RA Kousi M., Lehesjoki A.E., Mole S.E.; RT "Update of the mutation spectrum and clinical correlations of over 360 RT mutations in eight genes that underlie the neuronal ceroid RT lipofuscinoses."; RL Hum. Mutat. 33:42-63(2012). RN [14] RP CHARACTERIZATION OF VARIANT CLN5 ASN-230, SUBCELLULAR LOCATION (MEMBRANE RP FORM), TOPOLOGY, PROTEOLYTIC CLEAVAGE, AND GLYCOSYLATION. RX PubMed=24038957; DOI=10.1002/humu.22443; RA Larkin H., Ribeiro M.G., Lavoie C.; RT "Topology and membrane anchoring of the lysosomal storage disease-related RT protein CLN5."; RL Hum. Mutat. 34:1688-1697(2013). RN [15] RP CHARACTERIZATION OF VARIANTS CLN5 SER-143 AND ASN-230, GLYCOSYLATION AT RP ASN-130; ASN-143; ASN-178; ASN-203; ASN-255; ASN-271; ASN-281 AND ASN-352, RP MUTAGENESIS OF ASN-130; ASN-143; ASN-178; ASN-203; ASN-255; ASN-271; RP ASN-281 AND ASN-352, AND SUBCELLULAR LOCATION (SECRETED FORM). RX PubMed=24058541; DOI=10.1371/journal.pone.0074299; RA Moharir A., Peck S.H., Budden T., Lee S.Y.; RT "The role of N-glycosylation in folding, trafficking, and functionality of RT lysosomal protein CLN5."; RL PLoS ONE 8:E74299-E74299(2013). RN [16] RP CHARACTERIZATION OF VARIANT CLN5 ASN-230, AND PROTEOLYTIC CLEAVAGE AT RP C-TERMINUS. RX PubMed=26342652; DOI=10.1016/j.yexcr.2015.08.021; RA De Silva B., Adams J., Lee S.Y.; RT "Proteolytic processing of the neuronal ceroid lipofuscinosis related RT lysosomal protein CLN5."; RL Exp. Cell Res. 338:45-53(2015). RN [17] RP CHARACTERIZATION OF VARIANT CLN5 SER-143, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP SUBUNIT, CIRCULAR DICHROISM, MUTAGENESIS OF CYS-231 AND 318-HIS-LYS-319, RP SUBSTRATE SPECIFICITY, AND ACTIVE SITE. RX PubMed=37708259; DOI=10.1126/science.adg9288; RA Medoh U.N., Hims A., Chen J.Y., Ghoochani A., Nyame K., Dong W., RA Abu-Remaileh M.; RT "The Batten disease gene product CLN5 is the lysosomal RT bis(monoacylglycero)phosphate synthase."; RL Science 381:1182-1189(2023). CC -!- FUNCTION: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: CC Catalyzes the synthesis of bis(monoacylglycero)phosphate (BMP) via CC transacylation of 2 molecules of lysophosphatidylglycerol (LPG) CC (PubMed:37708259). BMP also known as lysobisphosphatidic acid plays a CC key role in the formation of intraluminal vesicles and in maintaining CC intracellular cholesterol homeostasis (PubMed:37708259). Can use only CC LPG as the exclusive lysophospholipid acyl donor for base exchange and CC displays BMP synthase activity towards various LPGs (LPG 14:0, LPG CC 16:0, LPG 18:0, LPG 18:1) with a higher preference for longer chain CC lengths (PubMed:37708259). Plays a role in influencing the retrograde CC trafficking of lysosomal sorting receptors SORT1 and IGF2R from the CC endosomes to the trans-Golgi network by controlling the recruitment of CC retromer complex to the endosomal membrane (PubMed:22431521). Regulates CC the localization and activation of RAB7A which is required to recruit CC the retromer complex to the endosomal membrane (PubMed:22431521). CC {ECO:0000269|PubMed:22431521, ECO:0000269|PubMed:37708259}. CC -!- FUNCTION: Exhibits palmitoyl protein thioesterase (S-depalmitoylation) CC activity in vitro and most likely plays a role in protein S- CC depalmitoylation. {ECO:0000269|PubMed:35427157}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + S-hexadecanoyl-L-cysteinyl-[protein] = H(+) + CC hexadecanoate + L-cysteinyl-[protein]; Xref=Rhea:RHEA:19233, CC Rhea:RHEA-COMP:10131, Rhea:RHEA-COMP:11032, ChEBI:CHEBI:7896, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:29950, CC ChEBI:CHEBI:74151; EC=3.1.2.22; CC Evidence={ECO:0000269|PubMed:35427157}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19234; CC Evidence={ECO:0000305|PubMed:35427157}; CC -!- CATALYTIC ACTIVITY: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: CC Reaction=2 a 3-acyl-sn-glycero-1-phospho-(1'-sn-glycerol) = a 3-acyl- CC sn-glycero-1-phospho-(3'-acyl-1'-sn-glycerol) + sn-glycero-1-phospho- CC (1'-sn-glycerol); Xref=Rhea:RHEA:77619, ChEBI:CHEBI:77717, CC ChEBI:CHEBI:197411, ChEBI:CHEBI:197425; CC Evidence={ECO:0000269|PubMed:37708259}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77620; CC Evidence={ECO:0000269|PubMed:37708259}; CC -!- CATALYTIC ACTIVITY: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: CC Reaction=2 3-(9Z-octadecenoyl)-sn-glycero-1-phospho-(1'-sn-glycerol) = CC 3-(9Z-octadecenoyl)-sn-glycero-1-phospho-(3'-(9Z-octadecenoyl)-1'-sn- CC glycerol) + sn-glycero-1-phospho-(1'-sn-glycerol); CC Xref=Rhea:RHEA:77599, ChEBI:CHEBI:139150, ChEBI:CHEBI:139152, CC ChEBI:CHEBI:197411; Evidence={ECO:0000269|PubMed:37708259}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77600; CC Evidence={ECO:0000269|PubMed:37708259}; CC -!- CATALYTIC ACTIVITY: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: CC Reaction=2 3-octadecanoyl-sn-glycero-1-phospho-(1'-sn-glycerol) = 3- CC octadecanoyl-sn-glycero-1-phospho-(3'-octadecanoyl-1'-sn-glycerol) + CC sn-glycero-1-phospho-(1'-sn-glycerol); Xref=Rhea:RHEA:77603, CC ChEBI:CHEBI:197411, ChEBI:CHEBI:197412, ChEBI:CHEBI:197414; CC Evidence={ECO:0000269|PubMed:37708259}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77604; CC Evidence={ECO:0000269|PubMed:37708259}; CC -!- CATALYTIC ACTIVITY: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: CC Reaction=2 3-hexadecanoyl-sn-glycero-1-phospho-(1'-sn-glycerol) = 3- CC hexadecanoyl-sn-glycero-1-phospho-(3'-hexadecanoyl-1'-sn-glycerol) + CC sn-glycero-1-phospho-(1'-sn-glycerol); Xref=Rhea:RHEA:77607, CC ChEBI:CHEBI:44859, ChEBI:CHEBI:197411, ChEBI:CHEBI:197415; CC Evidence={ECO:0000269|PubMed:37708259}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77608; CC Evidence={ECO:0000269|PubMed:37708259}; CC -!- CATALYTIC ACTIVITY: [Bis(monoacylglycero)phosphate synthase CLN5, secreted form]: CC Reaction=2 3-tetradecanoyl-sn-glycero-1-phospho-(1'-sn-glycerol) = 3- CC tetradecanoyl-sn-glycero-1-phospho-(3'-tetradecanoyl-1'-sn-glycerol) CC + sn-glycero-1-phospho-(1'-sn-glycerol); Xref=Rhea:RHEA:77611, CC ChEBI:CHEBI:197411, ChEBI:CHEBI:197413, ChEBI:CHEBI:197416; CC Evidence={ECO:0000269|PubMed:37708259}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77612; CC Evidence={ECO:0000269|PubMed:37708259}; CC -!- ACTIVITY REGULATION: Anionic phospholipids activate CC bis(monoacylglycero)phosphate (BMP) synthase activity CC (PubMed:37708259). Amiodarone, a cationic amphiphilic drug inhibits BMP CC synthase activity towards liposomal lysophosphatidylglycerol CC (PubMed:37708259). Palmostatin B inhibits palmitoyl protein CC thioesterase activity (PubMed:35427157). {ECO:0000269|PubMed:35427157, CC ECO:0000269|PubMed:37708259}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.3 uM for lysophosphatidylglycerol 18:1 (at pH 5) CC {ECO:0000269|PubMed:37708259}; CC KM=4.752 uM for lysophosphatidylglycerol 18:1 (at pH 6.5) CC {ECO:0000269|PubMed:37708259}; CC pH dependence: CC Optimum pH is 6.5 for bis(monoacylglycero)phosphate synthase activity CC (PubMed:37708259). Optimum pH of 6.5 and 8.5 is seen for palmitoyl CC thioesterase activity (PubMed:35427157). CC {ECO:0000269|PubMed:35427157, ECO:0000269|PubMed:37708259}; CC Temperature dependence: CC Thermostable. {ECO:0000269|PubMed:37708259}; CC -!- SUBUNIT: Multimer (PubMed:37708259). Interacts with SORT1, RAB5A and CC RAB7A (PubMed:22431521). Interacts with PPT1, TPP1, CLN3, CLN6, CLN8, CC ATP5F1A and ATP5F1B (By similarity). {ECO:0000250|UniProtKB:Q3UMW8, CC ECO:0000269|PubMed:22431521, ECO:0000269|PubMed:37708259}. CC -!- INTERACTION: CC O75503; Q13286: CLN3; NbExp=2; IntAct=EBI-1043514, EBI-3248760; CC -!- SUBCELLULAR LOCATION: [Bis(monoacylglycero)phosphate synthase CLN5, CC secreted form]: Lysosome {ECO:0000269|PubMed:11971870, CC ECO:0000269|PubMed:20052765, ECO:0000269|PubMed:22431521, CC ECO:0000269|PubMed:24038957, ECO:0000269|PubMed:24058541, CC ECO:0000269|PubMed:28442266, ECO:0000269|PubMed:37708259}. CC -!- SUBCELLULAR LOCATION: [Bis(monoacylglycero)phosphate synthase CLN5]: CC Membrane {ECO:0000269|PubMed:24038957, ECO:0000269|PubMed:28442266}; CC Single-pass type II membrane protein {ECO:0000269|PubMed:24038957, CC ECO:0000269|PubMed:28442266}. Note=An amphipathic anchor region CC facilitates its association with the membrane. CC {ECO:0000269|PubMed:24038957}. CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:9662406}. CC -!- PTM: N-glycosylated with both high mannose and complex type sugars. CC Glycosylation is important for proper folding and trafficking to the CC lysosomes. {ECO:0000269|PubMed:11971870, ECO:0000269|PubMed:20052765, CC ECO:0000269|PubMed:24038957, ECO:0000269|PubMed:24058541, CC ECO:0000269|PubMed:37708259}. CC -!- PTM: [Bis(monoacylglycero)phosphate synthase CLN5]: The type II CC membrane signal anchor is proteolytically cleaved to produce a mature CC form that is transported to the lysosomes CC (Bis(monoacylglycero)phosphate synthase CLN5, secreted form) CC (PubMed:24038957, PubMed:20052765, PubMed:28442266). CC {ECO:0000269|PubMed:20052765, ECO:0000269|PubMed:24038957, CC ECO:0000269|PubMed:28442266}. CC -!- PTM: Can undergo proteolytic cleavage at the C-terminus, probably by a CC cysteine protease and may involve the removal of approximately 10-15 CC residues from the C-terminal end (PubMed:26342652). CC {ECO:0000269|PubMed:26342652}. CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 5 (CLN5) [MIM:256731]: A form CC of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are CC progressive neurodegenerative, lysosomal storage diseases characterized CC by intracellular accumulation of autofluorescent liposomal material, CC and clinically by seizures, dementia, visual loss, and/or cerebral CC atrophy. The lipopigment patterns observed most often in neuronal CC ceroid lipofuscinosis type 5 comprise mixed combinations of granular, CC curvilinear, and fingerprint profiles. {ECO:0000269|PubMed:15728307, CC ECO:0000269|PubMed:16814585, ECO:0000269|PubMed:17607606, CC ECO:0000269|PubMed:19309691, ECO:0000269|PubMed:20052765, CC ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:24038957, CC ECO:0000269|PubMed:24058541, ECO:0000269|PubMed:26342652, CC ECO:0000269|PubMed:35427157, ECO:0000269|PubMed:37708259, CC ECO:0000269|PubMed:9662406}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the CLN5 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC27614.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NCL CLN5; Note=Neural Ceroid Lipofuscinoses mutation CC db; CC URL="https://www.ucl.ac.uk/ncl/cln5.shtml"; 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; AF068227; AAC27614.1; ALT_INIT; mRNA. DR EMBL; AK075109; BAG52069.1; -; mRNA. DR EMBL; AC001226; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS9456.2; -. DR RefSeq; NP_006484.1; NM_006493.2. DR PDB; 6R99; X-ray; 2.70 A; A=1-358. DR PDBsum; 6R99; -. DR AlphaFoldDB; O75503; -. DR SMR; O75503; -. DR BioGRID; 107614; 85. DR IntAct; O75503; 11. DR MINT; O75503; -. DR STRING; 9606.ENSP00000498772; -. DR GlyConnect; 1108; 17 N-Linked glycans (4 sites). DR GlyCosmos; O75503; 8 sites, 16 glycans. DR GlyGen; O75503; 9 sites, 16 N-linked glycans (4 sites), 1 O-linked glycan (1 site). DR iPTMnet; O75503; -. DR PhosphoSitePlus; O75503; -. DR SwissPalm; O75503; -. DR BioMuta; CLN5; -. DR EPD; O75503; -. DR jPOST; O75503; -. DR MassIVE; O75503; -. DR MaxQB; O75503; -. DR PaxDb; 9606-ENSP00000366673; -. DR PeptideAtlas; O75503; -. DR ProteomicsDB; 50054; -. DR Pumba; O75503; -. DR Antibodypedia; 50072; 197 antibodies from 24 providers. DR DNASU; 1203; -. DR Ensembl; ENST00000377453.9; ENSP00000366673.5; ENSG00000102805.16. DR Ensembl; ENST00000636183.2; ENSP00000490181.2; ENSG00000102805.16. DR GeneID; 1203; -. DR KEGG; hsa:1203; -. DR MANE-Select; ENST00000377453.9; ENSP00000366673.5; NM_006493.4; NP_006484.2. DR UCSC; uc058xoc.1; human. DR AGR; HGNC:2076; -. DR CTD; 1203; -. DR DisGeNET; 1203; -. DR GeneCards; CLN5; -. DR HGNC; HGNC:2076; CLN5. DR HPA; ENSG00000102805; Low tissue specificity. DR MalaCards; CLN5; -. DR MIM; 256731; phenotype. DR MIM; 608102; gene. DR neXtProt; NX_O75503; -. DR OpenTargets; ENSG00000102805; -. DR Orphanet; 79262; Adult neuronal ceroid lipofuscinosis. DR Orphanet; 168486; Congenital neuronal ceroid lipofuscinosis. DR Orphanet; 79263; Infantile neuronal ceroid lipofuscinosis. DR Orphanet; 79264; Juvenile neuronal ceroid lipofuscinosis. DR Orphanet; 168491; Late infantile neuronal ceroid lipofuscinosis. DR PharmGKB; PA26603; -. DR VEuPathDB; HostDB:ENSG00000102805; -. DR eggNOG; ENOG502QPQ5; Eukaryota. DR GeneTree; ENSGT00390000010065; -. DR HOGENOM; CLU_050387_0_0_1; -. DR InParanoid; O75503; -. DR OMA; FRPHQSF; -. DR OrthoDB; 2938611at2759; -. DR PhylomeDB; O75503; -. DR TreeFam; TF330864; -. DR PathwayCommons; O75503; -. DR SignaLink; O75503; -. DR BioGRID-ORCS; 1203; 9 hits in 1149 CRISPR screens. DR ChiTaRS; CLN5; human. DR GeneWiki; CLN5; -. DR GenomeRNAi; 1203; -. DR Pharos; O75503; Tbio. DR PRO; PR:O75503; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; O75503; Protein. DR Bgee; ENSG00000102805; Expressed in left lobe of thyroid gland and 190 other cell types or tissues. DR ExpressionAtlas; O75503; baseline and differential. DR GO; GO:0005829; C:cytosol; IEA:GOC. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005775; C:vacuolar lumen; IEA:Ensembl. DR GO; GO:0160121; F:bis(monoacylglycero)phosphate synthase activity; IDA:UniProtKB. DR GO; GO:0016798; F:hydrolase activity, acting on glycosyl bonds; IBA:GO_Central. DR GO; GO:0005537; F:mannose binding; IDA:UniProtKB. DR GO; GO:0016290; F:palmitoyl-CoA hydrolase activity; IDA:UniProtKB. DR GO; GO:0007420; P:brain development; IEP:UniProtKB. DR GO; GO:0070085; P:glycosylation; IDA:UniProtKB. DR GO; GO:0007042; P:lysosomal lumen acidification; IMP:UniProtKB. DR GO; GO:0007040; P:lysosome organization; IBA:GO_Central. DR GO; GO:0022008; P:neurogenesis; IEP:UniProtKB. DR GO; GO:0042551; P:neuron maturation; NAS:UniProtKB. DR GO; GO:1904426; P:positive regulation of GTP binding; IMP:UniProtKB. DR GO; GO:0030163; P:protein catabolic process; NAS:UniProtKB. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IMP:UniProtKB. DR GO; GO:0006465; P:signal peptide processing; IDA:UniProtKB. DR GO; GO:0007601; P:visual perception; IEA:Ensembl. DR InterPro; IPR026138; CLN5. DR PANTHER; PTHR15380:SF2; CEROID-LIPOFUSCINOSIS NEURONAL PROTEIN 5; 1. DR PANTHER; PTHR15380; CEROID-LIPOFUSCINOSIS, NEURONAL 5; 1. DR Pfam; PF15014; CLN5; 1. DR Genevisible; O75503; HS. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; Disulfide bond; Epilepsy; Glycoprotein; KW Hydrolase; Lysosome; Membrane; Neurodegeneration; KW Neuronal ceroid lipofuscinosis; Reference proteome; Signal-anchor; KW Transferase; Transmembrane; Transmembrane helix. FT CHAIN 1..358 FT /note="Bis(monoacylglycero)phosphate synthase CLN5" FT /id="PRO_0000089860" FT CHAIN 44..358 FT /note="Bis(monoacylglycero)phosphate synthase CLN5, FT secreted form" FT /id="PRO_0000438009" FT TOPO_DOM 1..23 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:24038957" FT TRANSMEM 24..40 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 41..358 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:24038957" FT REGION 304..343 FT /note="Membrane-anchoring" FT /evidence="ECO:0000269|PubMed:24038957" FT ACT_SITE 117 FT /note="Proton acceptor" FT /evidence="ECO:0000305|PubMed:35427157" FT ACT_SITE 231 FT /note="Nucleophile; Acyl-thioester intermediate" FT /evidence="ECO:0000305|PubMed:35427157, FT ECO:0000305|PubMed:37708259" FT SITE 43..44 FT /note="Cleavage; by SPPL3" FT /evidence="ECO:0000269|PubMed:28442266" FT CARBOHYD 130 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541, FT ECO:0000269|PubMed:35427157, ECO:0007744|PDB:6R99" FT CARBOHYD 143 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541, FT ECO:0000269|PubMed:35427157, ECO:0007744|PDB:6R99" FT CARBOHYD 178 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541" FT CARBOHYD 203 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541, FT ECO:0000269|PubMed:35427157, ECO:0007744|PDB:6R99" FT CARBOHYD 255 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541, FT ECO:0000269|PubMed:35427157, ECO:0007744|PDB:6R99" FT CARBOHYD 271 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541" FT CARBOHYD 281 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541" FT CARBOHYD 352 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:24058541" FT DISULFID 70..159 FT /evidence="ECO:0000269|PubMed:35427157" FT DISULFID 77..165 FT /evidence="ECO:0000269|PubMed:35427157" FT VARIANT 26 FT /note="W -> R (in dbSNP:rs199727787)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066895" FT VARIANT 63 FT /note="R -> H (in CLN5; retained in the endoplasmic FT reticulum rather than reaching the lysosome; FT dbSNP:rs104894386)" FT /evidence="ECO:0000269|PubMed:15728307, FT ECO:0000269|PubMed:20052765, ECO:0000269|PubMed:21990111" FT /id="VAR_042700" FT VARIANT 63 FT /note="R -> P (in CLN5; Retained in the endoplasmic FT reticulum rather than reaching the lysosome; FT dbSNP:rs104894386)" FT /evidence="ECO:0000269|PubMed:16814585, FT ECO:0000269|PubMed:20052765" FT /id="VAR_042702" FT VARIANT 77 FT /note="C -> Y (in CLN5; dbSNP:rs267606738)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066896" FT VARIANT 143 FT /note="N -> S (in CLN5; loss of glycosylation; effectively FT transported to the lysosome; significant loss of FT bis(monoacylglycero)phosphate synthase activity; no FT alterations in secondary structure and thermal stability; FT dbSNP:rs386833975)" FT /evidence="ECO:0000269|PubMed:21990111, FT ECO:0000269|PubMed:24058541" FT /id="VAR_066897" FT VARIANT 149 FT /note="L -> P (in CLN5; dbSNP:rs386833976)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066898" FT VARIANT 156 FT /note="P -> S (in CLN5; dbSNP:rs386833977)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066899" FT VARIANT 158 FT /note="W -> R (in CLN5; dbSNP:rs147065248)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066900" FT VARIANT 158 FT /note="W -> S (in CLN5; dbSNP:rs386833978)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066901" FT VARIANT 193 FT /note="N -> K (in dbSNP:rs138611001)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066902" FT VARIANT 209 FT /note="Y -> D (in CLN5; significant decrease in palmitoyl FT protein thioesterase activity; dbSNP:rs386833981)" FT /evidence="ECO:0000269|PubMed:17607606, FT ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:35427157" FT /id="VAR_042701" FT VARIANT 219 FT /note="E -> A (in dbSNP:rs11842935)" FT /id="VAR_059031" FT VARIANT 230 FT /note="D -> N (in CLN5; creates a new N-glycosylation site; FT retained in the endoplasmic reticulum rather than reaching FT the lysosome; significant decrease in palmitoyl protein FT thioesterase activity; dbSNP:rs28940280)" FT /evidence="ECO:0000269|PubMed:16814585, FT ECO:0000269|PubMed:20052765, ECO:0000269|PubMed:24038957, FT ECO:0000269|PubMed:24058541, ECO:0000269|PubMed:26342652, FT ECO:0000269|PubMed:35427157, ECO:0000269|PubMed:9662406" FT /id="VAR_005137" FT VARIANT 319 FT /note="K -> R (in dbSNP:rs1800209)" FT /evidence="ECO:0000269|PubMed:9662406" FT /id="VAR_005138" FT VARIANT 325 FT /note="Y -> C (in CLN5; dbSNP:rs148862100)" FT /evidence="ECO:0000269|PubMed:21990111" FT /id="VAR_066903" FT VARIANT 330 FT /note="W -> C (in CLN5; retained in the endoplasmic FT reticulum rather than reaching the lysosome; FT dbSNP:rs386833968)" FT /evidence="ECO:0000269|PubMed:19309691" FT /id="VAR_059032" FT MUTAGEN 101 FT /note="V->S: Significant decrease in palmitoyl protein FT thioesterase activity." FT /evidence="ECO:0000269|PubMed:35427157" FT MUTAGEN 115 FT /note="I->S: Significant decrease in palmitoyl protein FT thioesterase activity." FT /evidence="ECO:0000269|PubMed:35427157" FT MUTAGEN 117 FT /note="H->A: Significant decrease in palmitoyl protein FT thioesterase activity." FT /evidence="ECO:0000269|PubMed:35427157" FT MUTAGEN 130 FT /note="N->Q: Loss of glycosylation. Retained in the FT endoplasmic reticulum rather than reaching the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 143 FT /note="N->Q: Loss of glycosylation. Effectively transported FT to the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 178 FT /note="N->Q: Loss of glycosylation. Effectively transported FT to the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 203 FT /note="N->Q: Loss of glycosylation. Retained in the FT endoplasmic reticulum rather than reaching the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 231 FT /note="C->S: Significant decrease in FT bis(monoacylglycero)phosphate synthase and palmitoyl FT protein thioesterase activities. No alterations in FT secondary structure and thermal stability." FT /evidence="ECO:0000269|PubMed:35427157, FT ECO:0000269|PubMed:37708259" FT MUTAGEN 255 FT /note="N->Q: Loss of glycosylation. Retained in the FT endoplasmic reticulum rather than reaching the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 259 FT /note="I->S: Significant decrease in palmitoyl protein FT thioesterase activity." FT /evidence="ECO:0000269|PubMed:35427157" FT MUTAGEN 271 FT /note="N->Q: Loss of glycosylation. Retained in the FT endoplasmic reticulum rather than reaching the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 281 FT /note="N->Q: Loss of glycosylation. Partially retained in FT the endoplasmic reticulum." FT /evidence="ECO:0000269|PubMed:24058541" FT MUTAGEN 318..319 FT /note="HK->EE: Weakens vesicular FT bis(monoacylglycero)phosphate binding. No alterations in FT secondary structure and thermal stability." FT /evidence="ECO:0000269|PubMed:37708259" FT MUTAGEN 352 FT /note="N->Q: Loss of glycosylation. Retained in the Golgi FT apparatus rather than reaching the lysosome." FT /evidence="ECO:0000269|PubMed:24058541" FT CONFLICT 57 FT /note="Y -> C (in Ref. 2; BAG52069)" FT /evidence="ECO:0000305" FT CONFLICT 92 FT /note="I -> T (in Ref. 2; BAG52069)" FT /evidence="ECO:0000305" SQ SEQUENCE 358 AA; 41497 MW; 07E49D4913685190 CRC64; MAQEVDTAQG AEMRRGAGAA RGRASWCWAL ALLWLAVVPG WSRVSGIPSR RHWPVPYKRF DFRPKPDPYC QAKYTFCPTG SPIPVMEGDD DIEVFRLQAP VWEFKYGDLL GHLKIMHDAI GFRSTLTGKN YTMEWYELFQ LGNCTFPHLR PEMDAPFWCN QGAACFFEGI DDVHWKENGT LVQVATISGN MFNQMAKWVK QDNETGIYYE TWNVKASPEK GAETWFDSYD CSKFVLRTFN KLAEFGAEFK NIETNYTRIF LYSGEPTYLG NETSVFGPTG NKTLGLAIKR FYYPFKPHLP TKEFLLSLLQ IFDAVIVHKQ FYLFYNFEYW FLPMKFPFIK ITYEEIPLPI RNKTLSGL //