MCLN1_HUMAN
ID MCLN1_HUMAN Reviewed; 580 AA.
AC Q9GZU1; D6W647; Q7Z4F7; Q9H292; Q9H4B3; Q9H4B5;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Mucolipin-1 {ECO:0000303|PubMed:12459486};
DE Short=ML1;
DE AltName: Full=MG-2;
DE AltName: Full=Mucolipidin {ECO:0000303|PubMed:11013137};
DE AltName: Full=Transient receptor potential channel mucolipin 1;
DE Short=TRPML1 {ECO:0000303|PubMed:28112729};
GN Name=MCOLN1 {ECO:0000312|HGNC:HGNC:13356};
GN Synonyms=ML4, TRPML1 {ECO:0000303|PubMed:27623384}; ORFNames=MSTP080;
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], PROBABLE FUNCTION, TISSUE SPECIFICITY,
RP SUBCELLULAR LOCATION, AND INVOLVEMENT IN ML4.
RX PubMed=11013137; DOI=10.1086/321205;
RA Bassi M.T., Manzoni M., Monti E., Pizzo M.T., Ballabio A., Borsani G.;
RT "Cloning of the gene encoding a novel integral membrane protein,
RT mucolipidin, and identification of the two major founder mutations causing
RT mucolipidosis type IV.";
RL Am. J. Hum. Genet. 67:1110-1120(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], TISSUE SPECIFICITY, AND VARIANTS
RP ML4 TYR-362; PHE-408 DEL AND LEU-446.
RX PubMed=11030752; DOI=10.1093/hmg/9.17.2471;
RA Sun M., Goldin E., Stahl S., Falardeau J.L., Kennedy J.C.,
RA Acierno J.S. Jr., Bove C., Kaneski C.R., Nagle J., Bromley M.C., Colman M.,
RA Schiffmann R., Slaugenhaupt S.A.;
RT "Mucolipidosis type IV is caused by mutations in a gene encoding a novel
RT transient receptor potential channel.";
RL Hum. Mol. Genet. 9:2471-2478(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INVOLVEMENT IN ML4.
RX PubMed=10973263; DOI=10.1038/79095;
RA Bargal R., Avidan N., Ben-Asher E., Olender Z., Zeigler M., Frumkin A.,
RA Raas-Rothschild A., Glusman G., Lancet D., Bach G.;
RT "Identification of the gene causing mucolipidosis type IV.";
RL Nat. Genet. 26:118-123(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 391-580.
RC TISSUE=Aorta;
RA Xu H.S., Sheng H., Qin B.M., Liu Y.Q., Zhao B., Liu B., Wang X.Y.,
RA Zhang Q., Song L., Gao Y., Zhang C.L., Ye J., Ji X.J., Liu B.H., Lu H.,
RA Chen J.Z., Cai M.Q., Zheng W.Y., Teng C.Y., Liu Q., Yu L.T., Lin J.,
RA Gong Q., Zhang A.M., Gao R.L., Hui R.T.;
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP FUNCTIONAL CHARACTERIZATION, REGULATION BY CALCIUM, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12459486; DOI=10.1016/s0014-5793(02)03670-0;
RA LaPlante J.M., Falardeau J., Sun M., Kanazirska M., Brown E.M.,
RA Slaugenhaupt S.A., Vassilev P.M.;
RT "Identification and characterization of the single channel function of
RT human mucolipin-1 implicated in mucolipidosis type IV, a disorder affecting
RT the lysosomal pathway.";
RL FEBS Lett. 532:183-187(2002).
RN [9]
RP FUNCTION.
RX PubMed=15336987; DOI=10.1016/j.bbrc.2004.08.045;
RA LaPlante J.M., Ye C.P., Quinn S.J., Goldin E., Brown E.M.,
RA Slaugenhaupt S.A., Vassilev P.M.;
RT "Functional links between mucolipin-1 and Ca2+-dependent membrane
RT trafficking in mucolipidosis IV.";
RL Biochem. Biophys. Res. Commun. 322:1384-1391(2004).
RN [10]
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS ML4 PRO-232; PHE-408
RP DEL AND LEU-465.
RX PubMed=15178326; DOI=10.1016/j.febslet.2004.04.080;
RA Manzoni M., Monti E., Bresciani R., Bozzato A., Barlati S., Bassi M.T.,
RA Borsani G.;
RT "Overexpression of wild-type and mutant mucolipin proteins in mammalian
RT cells: effects on the late endocytic compartment organization.";
RL FEBS Lett. 567:219-224(2004).
RN [11]
RP FUNCTIONAL CHARACTERIZATION, SUBUNIT, AND CHARACTERIZATION OF VARIANTS ML4
RP TYR-362; PHE-408 DEL AND LEU-446.
RX PubMed=14749347; DOI=10.1093/hmg/ddh067;
RA Raychowdhury M.K., Gonzalez-Perrett S., Montalbetti N., Timpanaro G.A.,
RA Chasan B., Goldmann W.H., Stahl S., Cooney A., Goldin E., Cantiello H.F.;
RT "Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of
RT the mucolipin-1 cation channel.";
RL Hum. Mol. Genet. 13:617-627(2004).
RN [12]
RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ARG-200.
RX PubMed=16257972; DOI=10.1074/jbc.m508210200;
RA Kiselyov K., Chen J., Rbaibi Y., Oberdick D., Tjon-Kon-Sang S.,
RA Shcheynikov N., Muallem S., Soyombo A.;
RT "TRP-ML1 is a lysosomal monovalent cation channel that undergoes
RT proteolytic cleavage.";
RL J. Biol. Chem. 280:43218-43223(2005).
RN [13]
RP DILEUCINE MOTIFS, SUBCELLULAR LOCATION, PALMITOYLATION, AND MUTAGENESIS OF
RP LEU-15; 15-LEU-LEU-16; 565-CYS--CYS-567; LEU-577 AND 577-LEU-LEU-578.
RX PubMed=16497227; DOI=10.1111/j.1600-0854.2006.00387.x;
RA Vergarajauregui S., Puertollano R.;
RT "Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes.";
RL Traffic 7:337-353(2006).
RN [14]
RP FUNCTION, MUTAGENESIS OF ASP-471, SUBCELLULAR LOCATION, AND
RP CHARACTERIZATION OF VARIANT ML4 LEU-465.
RX PubMed=16978393; DOI=10.1111/j.1600-0854.2006.00475.x;
RA Pryor P.R., Reimann F., Gribble F.M., Luzio J.P.;
RT "Mucolipin-1 is a lysosomal membrane protein required for intracellular
RT lactosylceramide traffic.";
RL Traffic 7:1388-1398(2006).
RN [15]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RC TISSUE=Placenta;
RX PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x;
RA Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B., Schaefer H.,
RA Elsaesser H.-P., Mann M., Hasilik A.;
RT "Integral and associated lysosomal membrane proteins.";
RL Traffic 8:1676-1686(2007).
RN [16]
RP PHOSPHORYLATION AT SER-557 AND SER-559.
RX PubMed=17988215; DOI=10.1042/bj20070713;
RA Vergarajauregui S., Oberdick R., Kiselyov K., Puertollano R.;
RT "Mucolipin 1 channel activity is regulated by protein kinase A-mediated
RT phosphorylation.";
RL Biochem. J. 410:417-425(2008).
RN [17]
RP FUNCTION, MUTAGENESIS OF VAL-432, AND CHARACTERIZATION OF VARIANTS ML4
RP PRO-232; TYR-362; CYS-403 AND LEU-446.
RX PubMed=18794901; DOI=10.1038/nature07311;
RA Dong X.P., Cheng X., Mills E., Delling M., Wang F., Kurz T., Xu H.;
RT "The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal
RT iron release channel.";
RL Nature 455:992-996(2008).
RN [18]
RP INTERACTION WITH PDCD6, AND MUTAGENESIS OF ARG-44; LEU-45; 44-ARG--LYS-46
RP AND 47-TYR--PHE-49.
RX PubMed=19864416; DOI=10.1074/jbc.m109.047241;
RA Vergarajauregui S., Martina J.A., Puertollano R.;
RT "Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent
RT interactor of mucolipin-1.";
RL J. Biol. Chem. 284:36357-36366(2009).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-230.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [20]
RP SUBUNIT.
RX PubMed=19885840; DOI=10.1002/jcp.21956;
RA Curcio-Morelli C., Zhang P., Venugopal B., Charles F.A., Browning M.F.,
RA Cantiello H.F., Slaugenhaupt S.A.;
RT "Functional multimerization of mucolipin channel proteins.";
RL J. Cell. Physiol. 222:328-335(2010).
RN [21]
RP FUNCTION, MUTAGENESIS OF TYR-109, AND CHARACTERIZATION OF VARIANTS ML4
RP PRO-106 AND LEU-465.
RX PubMed=21256127; DOI=10.1016/j.yexcr.2011.01.008;
RA LaPlante J.M., Falardeau J.L., Brown E.M., Slaugenhaupt S.A.,
RA Vassilev P.M.;
RT "The cation channel mucolipin-1 is a bifunctional protein that facilitates
RT membrane remodeling via its serine lipase domain.";
RL Exp. Cell Res. 317:691-705(2011).
RN [22]
RP INTERACTION WITH LAPTM4B, AND SUBCELLULAR LOCATION.
RX PubMed=21224396; DOI=10.1242/jcs.076240;
RA Vergarajauregui S., Martina J.A., Puertollano R.;
RT "LAPTMs regulate lysosomal function and interact with mucolipin 1: new
RT clues for understanding mucolipidosis type IV.";
RL J. Cell Sci. 124:459-468(2011).
RN [23]
RP ACTIVITY REGULATION, PHOSPHOINOSITIDE-BINDING, AND MUTAGENESIS OF
RP 42-ARG--ARG-44 AND 61-ARG-LYS-62.
RX PubMed=22733759; DOI=10.1073/pnas.1202194109;
RA Zhang X., Li X., Xu H.;
RT "Phosphoinositide isoforms determine compartment-specific ion channel
RT activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:11384-11389(2012).
RN [24]
RP FUNCTION, AND INTERACTION WITH TMEM163.
RX PubMed=25130899; DOI=10.1111/tra.12205;
RA Cuajungco M.P., Basilio L.C., Silva J., Hart T., Tringali J., Chen C.C.,
RA Biel M., Grimm C.;
RT "Cellular zinc levels are modulated by TRPML1-TMEM163 interaction.";
RL Traffic 15:1247-1265(2014).
RN [25]
RP FUNCTION.
RX PubMed=25733853; DOI=10.1073/pnas.1419669112;
RA Wang W., Gao Q., Yang M., Zhang X., Yu L., Lawas M., Li X.,
RA Bryant-Genevier M., Southall N.T., Marugan J., Ferrer M., Xu H.;
RT "Up-regulation of lysosomal TRPML1 channels is essential for lysosomal
RT adaptation to nutrient starvation.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:E1373-E1381(2015).
RN [26]
RP FUNCTION.
RX PubMed=27623384; DOI=10.1016/j.devcel.2016.08.001;
RA Krishna S., Palm W., Lee Y., Yang W., Bandyopadhyay U., Xu H., Florey O.,
RA Thompson C.B., Overholtzer M.;
RT "PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following
RT Engulfment.";
RL Dev. Cell 38:536-547(2016).
RN [27]
RP FUNCTION.
RX PubMed=27787197; DOI=10.7554/elife.19360;
RA Li R.J., Xu J., Fu C., Zhang J., Zheng Y.G., Jia H., Liu J.O.;
RT "Regulation of mTORC1 by lysosomal calcium and calmodulin.";
RL Elife 5:0-0(2016).
RN [28]
RP FUNCTION.
RX PubMed=27357649; DOI=10.1038/ncomms12109;
RA Zhang X., Cheng X., Yu L., Yang J., Calvo R., Patnaik S., Hu X., Gao Q.,
RA Yang M., Lawas M., Delling M., Marugan J., Ferrer M., Xu H.;
RT "MCOLN1 is a ROS sensor in lysosomes that regulates autophagy.";
RL Nat. Commun. 7:12109-12109(2016).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 84-296, EXTRACELLULAR/LUMENAL
RP PORE-FORMING DOMAIN, SUBUNIT, ACTIVITY REGULATION, MUTAGENESIS OF SER-110;
RP ASP-111; GLY-112; ALA-113; ASP-114; ASP-115; LEU-144; ARG-146 AND VAL-432,
RP AND CHARACTERIZATION OF VARIANTS ML4 PRO-106 AND PRO-232.
RX PubMed=28112729; DOI=10.1038/nsmb.3362;
RA Li M., Zhang W.K., Benvin N.M., Zhou X., Su D., Li H., Wang S.,
RA Michailidis I.E., Tong L., Li X., Yang J.;
RT "Structural basis of dual Ca(2+)/pH regulation of the endolysosomal TRPML1
RT channel.";
RL Nat. Struct. Mol. Biol. 24:205-213(2017).
RN [30] {ECO:0007744|PDB:5WJ5, ECO:0007744|PDB:5WJ9}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.49 ANGSTROMS), FUNCTION, ACTIVITY
RP REGULATION, SUBUNIT, DISULFIDE BONDS, TOPOLOGY, AND MUTAGENESIS OF LEU-15
RP AND LEU-577.
RX PubMed=29019983; DOI=10.1038/nature24036;
RA Schmiege P., Fine M., Blobel G., Li X.;
RT "Human TRPML1 channel structures in open and closed conformations.";
RL Nature 550:366-370(2017).
RN [31]
RP VARIANTS ML4 PRO-232; PHE-408 DEL AND LEU-465.
RX PubMed=11317355; DOI=10.1002/humu.1115;
RA Bargal R., Avidan N., Olender Z., Ben-Asher E., Zeigler M.,
RA Raas-Rothschild A., Frumkin A., Ben-Yoseph O., Friedlender Y., Lancet D.,
RA Bach G.;
RT "Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish
RT patients and the frequency of the disease in the Ashkenazi Jewish
RT population.";
RL Hum. Mutat. 17:397-402(2001).
RN [32]
RP VARIANTS ML4 PRO-106; TYR-362; PHE-408 DEL AND PRO-447.
RX PubMed=12182165; DOI=10.1212/wnl.59.3.306;
RA Altarescu G., Sun M., Moore D.F., Smith J.A., Wiggs E.A., Solomon B.I.,
RA Patronas N.J., Frei K.P., Gupta S., Kaneski C.R., Quarrell O.W.,
RA Slaugenhaupt S.A., Goldin E., Schiffmann R.;
RT "The neurogenetics of mucolipidosis type IV.";
RL Neurology 59:306-313(2002).
RN [33]
RP VARIANT ML4 CYS-403.
RX PubMed=15523648; DOI=10.1002/humu.20094;
RA Goldin E., Stahl S., Cooney A.M., Kaneski C.R., Gupta S., Brady R.O.,
RA Ellis J.R., Schiffmann R.;
RT "Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited
RT case of mucolipidosis IV.";
RL Hum. Mutat. 24:460-465(2004).
RN [34]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-331.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Nonselective cation channel probably playing a role in the
CC regulation of membrane trafficking events and of metal homeostasis.
CC Proposed to play a major role in Ca(2+) release from late endosome and
CC lysosome vesicles to the cytoplasm, which is important for many
CC lysosome-dependent cellular events, including the fusion and
CC trafficking of these organelles, exocytosis and autophagy
CC (PubMed:11013137, PubMed:12459486, PubMed:15336987, PubMed:14749347,
CC PubMed:29019983, PubMed:27623384). Required for efficient uptake of
CC large particles in macrophages in which Ca(2+) release from the
CC lysosomes triggers lysosomal exocytosis. May also play a role in
CC phagosome-lysosome fusion (By similarity). Involved in lactosylceramide
CC trafficking indicative for a role in the regulation of late endocytic
CC membrane fusion/fission events (PubMed:16978393). By mediating
CC lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling
CC and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues
CC such as nutrient levels (PubMed:27787197, PubMed:25733853). Seems to
CC act as lysosomal active oxygen species (ROS) sensor involved in ROS-
CC induced TFEB activation and autophagy (PubMed:27357649). Functions as a
CC Fe(2+) permeable channel in late endosomes and lysosomes
CC (PubMed:18794901). Proposed to play a role in zinc homeostasis probably
CC implicating its association with TMEM163 (PubMed:25130899) In adaptive
CC immunity, TRPML2 and TRPML1 may play redundant roles in the function of
CC the specialized lysosomes of B cells (By similarity).
CC {ECO:0000250|UniProtKB:Q99J21, ECO:0000269|PubMed:12459486,
CC ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15336987,
CC ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901,
CC ECO:0000269|PubMed:25130899, ECO:0000269|PubMed:25733853,
CC ECO:0000269|PubMed:27357649, ECO:0000269|PubMed:27623384,
CC ECO:0000269|PubMed:27787197, ECO:0000269|PubMed:29019983,
CC ECO:0000305|PubMed:11013137}.
CC -!- FUNCTION: May contribute to cellular lipase activity within the late
CC endosomal pathway or at the cell surface which may be involved in
CC processes of membrane reshaping and vesiculation, especially the growth
CC of tubular structures. However, it is not known, whether it conveys the
CC enzymatic activity directly, or merely facilitates the activity of an
CC associated phospholipase. {ECO:0000305|PubMed:21256127}.
CC -!- ACTIVITY REGULATION: Channel activity is controlled by multiple
CC regulatory mechanisms in different subcellular compartments. Channel
CC function is transiently modulated by changes in Ca(2+), and inhibited
CC by a reduction of pH; pH changes modify the aggregation state of
CC unitary channels; a negative cooperativity between
CC extracellular/lumenal Ca(2+) and H(+) is suggested (PubMed:12459486,
CC PubMed:28112729). Regulated by phosphoinositides in a compartment-
CC specific manner: in lysosomes activated by PtdIns(3,5)P2
CC (Phosphatidylinositol 3,5-bisphosphate) and at the plasma membrane
CC inhibited by PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate)
CC (PubMed:22733759, PubMed:29019983). {ECO:0000269|PubMed:12459486,
CC ECO:0000269|PubMed:22733759, ECO:0000269|PubMed:28112729,
CC ECO:0000269|PubMed:29019983}.
CC -!- SUBUNIT: Homotetramer (PubMed:28112729, PubMed:29019983). Homooligomer
CC (PubMed:14749347). Can heterooligomerize with MCOLN2 or MCOLN3;
CC heteromeric assemblies have different channel properties as compared to
CC the respective homooligomers and may be tissue-specific
CC (PubMed:19885840). Interacts with PDCD6 (PubMed:19864416). Interacts
CC with TMEM163 (PubMed:25130899). Interacts with LAPTM4B
CC (PubMed:21224396). {ECO:0000269|PubMed:14749347,
CC ECO:0000269|PubMed:19864416, ECO:0000269|PubMed:19885840,
CC ECO:0000269|PubMed:21224396, ECO:0000269|PubMed:25130899,
CC ECO:0000269|PubMed:29019983, ECO:0000305|PubMed:28112729}.
CC -!- INTERACTION:
CC Q9GZU1; Q92624: APPBP2; NbExp=3; IntAct=EBI-721209, EBI-743771;
CC Q9GZU1; Q9GZU1: MCOLN1; NbExp=3; IntAct=EBI-721209, EBI-721209;
CC Q9GZU1; Q96IW7: SEC22A; NbExp=3; IntAct=EBI-721209, EBI-8652744;
CC -!- SUBCELLULAR LOCATION: Late endosome membrane
CC {ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:21224396}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:29019983}. Lysosome membrane
CC {ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:21224396,
CC ECO:0000305|PubMed:16497227, ECO:0000305|PubMed:16978393}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:29019983}. Cytoplasmic vesicle
CC membrane {ECO:0000269|PubMed:12459486}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29019983}. Cell projection, phagocytic cup
CC {ECO:0000250|UniProtKB:Q99J21}. Cytoplasmic vesicle, phagosome membrane
CC {ECO:0000250|UniProtKB:Q99J21}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29019983}. Cell membrane
CC {ECO:0000305|PubMed:29019983}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29019983}. Note=Delivery from the trans-Golgi to
CC lysosomes seems to occur mainly in a direct intracellular manner
CC without intermediate delivery to the plasma membrane (PubMed:16497227).
CC Under normal conditions, restricted to intracellular compartments so
CC that only a very minor proportion is present at the cell membrane
CC (PubMed:12459486, PubMed:18794901, PubMed:28112729, PubMed:29019983).
CC {ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:18794901,
CC ECO:0000269|PubMed:28112729, ECO:0000269|PubMed:29019983,
CC ECO:0000305|PubMed:16497227}.
CC -!- TISSUE SPECIFICITY: Widely expressed in adult and fetal tissues.
CC {ECO:0000269|PubMed:10973263, ECO:0000269|PubMed:11013137,
CC ECO:0000269|PubMed:11030752}.
CC -!- DOMAIN: The most N-terminal extracellular/lumenal domain (referred to
CC as I-II linker or polycystin-mucolipin domain) contributes to a
CC structure with a four-fold rotational symmetry in a tetrameric
CC assembly; the structure contains a central highly electronegative pore
CC with a 14 A diameter. The pore is critical for Ca(2+) and pH
CC regulation. The protruding structure formed by the I-II linkers may
CC contain all the interaction sites with lipids and proteins in the
CC endolysosomal lumen. {ECO:0000269|PubMed:28112729}.
CC -!- PTM: Palmitoylated; involved in association with membranes.
CC {ECO:0000269|PubMed:16497227}.
CC -!- PTM: Phosphorylation by PKA inhibits channel activity.
CC Dephosphorylation increases activity. {ECO:0000269|PubMed:17988215}.
CC -!- PTM: Proteolytically cleaved probably involving multiple lysosomal
CC proteases including cathepsin B; inhibits lysosomal channel activity
CC (PubMed:16257972). {ECO:0000269|PubMed:16257972}.
CC -!- DISEASE: Mucolipidosis 4 (ML4) [MIM:252650]: An autosomal recessive
CC lysosomal storage disorder characterized by severe psychomotor
CC retardation and ophthalmologic abnormalities, including corneal
CC opacity, retinal degeneration and strabismus. Storage bodies of lipids
CC and water-soluble substances are seen by electron microscopy in almost
CC every cell type of the patients. Most patients are unable to speak or
CC walk independently and reach a maximal developmental level of 1-2
CC years. All patients have constitutive achlorhydia associated with a
CC secondary elevation of serum gastrin levels.
CC {ECO:0000269|PubMed:10973263, ECO:0000269|PubMed:11013137,
CC ECO:0000269|PubMed:11030752, ECO:0000269|PubMed:11317355,
CC ECO:0000269|PubMed:12182165, ECO:0000269|PubMed:14749347,
CC ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:15523648,
CC ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901,
CC ECO:0000269|PubMed:21256127, ECO:0000269|PubMed:28112729}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family.
CC Polycystin subfamily. MCOLN1 sub-subfamily. {ECO:0000305}.
CC -!- CAUTION: There are conflicting results relative to ion selectivity and
CC permeation. Initially outward rectification has been reported which
CC makes the proposed activity as lysosymal Ca(2+) release channel
CC unlikely. Inward rectification has been decribed in later studies
CC supporting the Ca(2+) release activity. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAQ13604.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAC07813.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};
CC Sequence=EAW69031.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=EAW69034.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
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DR EMBL; AJ293659; CAC07813.1; ALT_SEQ; mRNA.
DR EMBL; AJ293970; CAC08215.1; -; mRNA.
DR EMBL; AF287269; AAG00797.1; -; mRNA.
DR EMBL; AF287270; AAG00798.1; -; Genomic_DNA.
DR EMBL; AF249319; AAG10422.1; -; mRNA.
DR EMBL; AF305579; AAG42242.1; -; Genomic_DNA.
DR EMBL; AF305572; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AF305573; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AF305574; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AF305575; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AF305576; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AF305577; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AF305578; AAG42242.1; JOINED; Genomic_DNA.
DR EMBL; AK026102; BAB15360.1; -; mRNA.
DR EMBL; CH471139; EAW69031.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471139; EAW69034.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC005149; AAH05149.1; -; mRNA.
DR EMBL; AF171088; AAQ13604.1; ALT_INIT; mRNA.
DR CCDS; CCDS12180.1; -.
DR RefSeq; NP_065394.1; NM_020533.2.
DR PDB; 5TJA; X-ray; 2.30 A; A=84-296.
DR PDB; 5TJB; X-ray; 2.40 A; A=84-296.
DR PDB; 5TJC; X-ray; 2.40 A; A=84-296.
DR PDB; 5WJ5; EM; 3.70 A; A/B/C/D=1-580.
DR PDB; 5WJ9; EM; 3.49 A; A/B/C/D=1-580.
DR PDB; 6E7P; EM; 3.50 A; A/B/C/D=1-580.
DR PDB; 6E7Y; EM; 3.57 A; A/B/C/D=1-580.
DR PDB; 6E7Z; EM; 3.73 A; A/B/C/D=1-580.
DR PDB; 7MGL; EM; 2.90 A; A/B/C/D=1-580.
DR PDBsum; 5TJA; -.
DR PDBsum; 5TJB; -.
DR PDBsum; 5TJC; -.
DR PDBsum; 5WJ5; -.
DR PDBsum; 5WJ9; -.
DR PDBsum; 6E7P; -.
DR PDBsum; 6E7Y; -.
DR PDBsum; 6E7Z; -.
DR PDBsum; 7MGL; -.
DR AlphaFoldDB; Q9GZU1; -.
DR SMR; Q9GZU1; -.
DR BioGRID; 121441; 18.
DR DIP; DIP-62090N; -.
DR ELM; Q9GZU1; -.
DR IntAct; Q9GZU1; 8.
DR MINT; Q9GZU1; -.
DR STRING; 9606.ENSP00000264079; -.
DR ChEMBL; CHEMBL4524043; -.
DR GuidetoPHARMACOLOGY; 501; -.
DR TCDB; 1.A.5.3.1; the polycystin cation channel (pcc) family.
DR GlyGen; Q9GZU1; 2 sites.
DR iPTMnet; Q9GZU1; -.
DR PhosphoSitePlus; Q9GZU1; -.
DR SwissPalm; Q9GZU1; -.
DR BioMuta; MCOLN1; -.
DR DMDM; 50401163; -.
DR EPD; Q9GZU1; -.
DR jPOST; Q9GZU1; -.
DR MassIVE; Q9GZU1; -.
DR MaxQB; Q9GZU1; -.
DR PaxDb; Q9GZU1; -.
DR PeptideAtlas; Q9GZU1; -.
DR PRIDE; Q9GZU1; -.
DR ProteomicsDB; 80143; -.
DR Antibodypedia; 12053; 167 antibodies from 22 providers.
DR DNASU; 57192; -.
DR Ensembl; ENST00000264079.11; ENSP00000264079.5; ENSG00000090674.16.
DR GeneID; 57192; -.
DR KEGG; hsa:57192; -.
DR MANE-Select; ENST00000264079.11; ENSP00000264079.5; NM_020533.3; NP_065394.1.
DR UCSC; uc002mgo.4; human.
DR CTD; 57192; -.
DR DisGeNET; 57192; -.
DR GeneCards; MCOLN1; -.
DR GeneReviews; MCOLN1; -.
DR HGNC; HGNC:13356; MCOLN1.
DR HPA; ENSG00000090674; Low tissue specificity.
DR MalaCards; MCOLN1; -.
DR MIM; 252650; phenotype.
DR MIM; 605248; gene.
DR neXtProt; NX_Q9GZU1; -.
DR OpenTargets; ENSG00000090674; -.
DR Orphanet; 578; Mucolipidosis type IV.
DR PharmGKB; PA30699; -.
DR VEuPathDB; HostDB:ENSG00000090674; -.
DR eggNOG; KOG3733; Eukaryota.
DR GeneTree; ENSGT00950000183036; -.
DR HOGENOM; CLU_020945_1_1_1; -.
DR InParanoid; Q9GZU1; -.
DR OMA; DKYLAIP; -.
DR OrthoDB; 1379516at2759; -.
DR PhylomeDB; Q9GZU1; -.
DR TreeFam; TF317783; -.
DR PathwayCommons; Q9GZU1; -.
DR Reactome; R-HSA-3295583; TRP channels.
DR Reactome; R-HSA-917977; Transferrin endocytosis and recycling.
DR SignaLink; Q9GZU1; -.
DR SIGNOR; Q9GZU1; -.
DR BioGRID-ORCS; 57192; 20 hits in 1083 CRISPR screens.
DR ChiTaRS; MCOLN1; human.
DR GeneWiki; MCOLN1; -.
DR GenomeRNAi; 57192; -.
DR Pharos; Q9GZU1; Tchem.
DR PRO; PR:Q9GZU1; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9GZU1; protein.
DR Bgee; ENSG00000090674; Expressed in spleen and 172 other tissues.
DR ExpressionAtlas; Q9GZU1; baseline and differential.
DR Genevisible; Q9GZU1; HS.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; NAS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0001891; C:phagocytic cup; IEA:UniProtKB-SubCell.
DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0005262; F:calcium channel activity; TAS:Reactome.
DR GO; GO:0005261; F:cation channel activity; NAS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0097682; F:intracellular phosphatidylinositol-3,5-bisphosphate-sensitive cation channel activity; ISS:UniProtKB.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0099604; F:ligand-gated calcium channel activity; IDA:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0072345; F:NAADP-sensitive calcium-release channel activity; IBA:GO_Central.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0097352; P:autophagosome maturation; IEA:Ensembl.
DR GO; GO:0070588; P:calcium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006812; P:cation transport; NAS:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; ISS:UniProtKB.
DR GO; GO:0071467; P:cellular response to pH; ISS:UniProtKB.
DR GO; GO:0090382; P:phagosome maturation; IDA:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR GO; GO:0033572; P:transferrin transport; TAS:Reactome.
DR InterPro; IPR039031; Mucolipin.
DR InterPro; IPR013122; PKD1_2_channel.
DR PANTHER; PTHR12127; PTHR12127; 1.
DR Pfam; PF08016; PKD_channel; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Adaptive immunity; Calcium; Calcium transport; Cell membrane;
KW Cell projection; Cytoplasmic vesicle; Disease variant; Disulfide bond;
KW Endosome; Glycoprotein; Immunity; Ion channel; Ion transport;
KW Lipid-binding; Lipoprotein; Lysosome; Membrane; Mucolipidosis; Palmitate;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1..580
FT /note="Mucolipin-1"
FT /id="PRO_0000215362"
FT TOPO_DOM 1..65
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TRANSMEM 66..86
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 87..298
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TRANSMEM 299..321
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 322..350
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TRANSMEM 351..371
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 372..382
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TRANSMEM 383..405
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 406..427
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TRANSMEM 428..448
FT /note="Helical; Name=5"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 449..456
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019983"
FT INTRAMEM 457..477
FT /note="Pore-forming"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 478..491
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TRANSMEM 492..513
FT /note="Helical; Name=6"
FT /evidence="ECO:0000269|PubMed:29019983"
FT TOPO_DOM 514..580
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019983"
FT REGION 1..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 42..62
FT /note="Interaction with phosphoinositides"
FT /evidence="ECO:0000269|PubMed:22733759"
FT REGION 107..121
FT /note="Extracellular/lumenal pore loop"
FT /evidence="ECO:0000305|PubMed:28112729"
FT REGION 565..567
FT /note="Required for palmitoylation and association with
FT membranes"
FT /evidence="ECO:0000269|PubMed:16497227"
FT MOTIF 11..16
FT /note="Dileucine motif; mediates targeting to lysosomes"
FT /evidence="ECO:0000269|PubMed:16497227"
FT MOTIF 469..474
FT /note="Selectivity filter"
FT /evidence="ECO:0000305|PubMed:29019983"
FT MOTIF 573..578
FT /note="Dileucine internalization motif; mediates AP2
FT complex-dependent internalization"
FT /evidence="ECO:0000269|PubMed:16497227"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99J21"
FT MOD_RES 557
FT /note="Phosphoserine; by PAK"
FT /evidence="ECO:0000269|PubMed:17988215"
FT MOD_RES 559
FT /note="Phosphoserine; by PAK"
FT /evidence="ECO:0000269|PubMed:17988215"
FT CARBOHYD 230
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT DISULFID 166..192
FT /evidence="ECO:0000269|PubMed:28112729,
FT ECO:0000269|PubMed:29019983, ECO:0007744|PDB:5TJA,
FT ECO:0007744|PDB:5TJB, ECO:0007744|PDB:5TJC,
FT ECO:0007744|PDB:5WJ5, ECO:0007744|PDB:5WJ9"
FT DISULFID 253..284
FT /evidence="ECO:0000269|PubMed:28112729,
FT ECO:0000269|PubMed:29019983, ECO:0007744|PDB:5TJA,
FT ECO:0007744|PDB:5TJB, ECO:0007744|PDB:5TJC,
FT ECO:0007744|PDB:5WJ5, ECO:0007744|PDB:5WJ9"
FT VARIANT 106
FT /note="L -> P (in ML4; decreases formation and extrusion of
FT tubulo-vesicular structures when overexpressed; disrupts
FT tetrameric assembly; abolishes lysosomal localization;
FT dbSNP:rs797044825)"
FT /evidence="ECO:0000269|PubMed:12182165,
FT ECO:0000269|PubMed:21256127, ECO:0000269|PubMed:28112729"
FT /id="VAR_019369"
FT VARIANT 232
FT /note="T -> P (in ML4; fails to localize to late endosomes;
FT abolishes Fe(2+) permeability; disrupts tetrameric
FT assembly; abolishes lysosomal localization;
FT dbSNP:rs767122713)"
FT /evidence="ECO:0000269|PubMed:11317355,
FT ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:18794901,
FT ECO:0000269|PubMed:28112729"
FT /id="VAR_019370"
FT VARIANT 331
FT /note="V -> L (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036453"
FT VARIANT 362
FT /note="D -> Y (in ML4; affects channel activity; abolishes
FT Fe(2+) permeability; dbSNP:rs121908372)"
FT /evidence="ECO:0000269|PubMed:11030752,
FT ECO:0000269|PubMed:12182165, ECO:0000269|PubMed:14749347,
FT ECO:0000269|PubMed:18794901"
FT /id="VAR_019371"
FT VARIANT 403
FT /note="R -> C (in ML4; impairs Fe(2+) permeability;
FT dbSNP:rs121908374)"
FT /evidence="ECO:0000269|PubMed:15523648,
FT ECO:0000269|PubMed:18794901"
FT /id="VAR_038380"
FT VARIANT 408
FT /note="Missing (in ML4; mild psychomotor involvement; does
FT not affect channel activity; affects channel inhibition by
FT low pH; still localizes to late endosomes;
FT dbSNP:rs797044817)"
FT /evidence="ECO:0000269|PubMed:11030752,
FT ECO:0000269|PubMed:11317355, ECO:0000269|PubMed:12182165,
FT ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15178326"
FT /id="VAR_019372"
FT VARIANT 446
FT /note="V -> L (in ML4; does not affect channel activity;
FT affects channel inhibition by low pH; impairs Fe(2+)
FT permeability; dbSNP:rs754097561)"
FT /evidence="ECO:0000269|PubMed:11030752,
FT ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:18794901"
FT /id="VAR_019373"
FT VARIANT 447
FT /note="L -> P (in ML4; dbSNP:rs797044827)"
FT /evidence="ECO:0000269|PubMed:12182165"
FT /id="VAR_019374"
FT VARIANT 465
FT /note="F -> L (in ML4; still localizes to late endosomes;
FT fails to rescue defect of lactosylceramide traffic through
FT the late endocytic pathway in ML4 patient cells; minor
FT effect on formation and extrusion of tubulo-vesicular
FT structures when overexpressed; dbSNP:rs797044828)"
FT /evidence="ECO:0000269|PubMed:11317355,
FT ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:16978393,
FT ECO:0000269|PubMed:21256127"
FT /id="VAR_019375"
FT MUTAGEN 15..16
FT /note="LL->AA: No effect on localization to lysosomes."
FT /evidence="ECO:0000269|PubMed:16497227"
FT MUTAGEN 15
FT /note="L->A: Abolishes localization to lysosomes and leads
FT to expression at the cell membrane; when associated with A-
FT 577."
FT /evidence="ECO:0000269|PubMed:16497227,
FT ECO:0000269|PubMed:29019983"
FT MUTAGEN 42..44
FT /note="RRR->AAA: Reduces PtdIns(4,5)P2 sensitivity."
FT /evidence="ECO:0000269|PubMed:22733759"
FT MUTAGEN 44..46
FT /note="RLK->AAA: Abolishes interaction with PDCD6 and
FT decreases formation of aberrant endosomes upon
FT overexpression."
FT /evidence="ECO:0000269|PubMed:19864416"
FT MUTAGEN 44
FT /note="R->A: Abolishes interaction with PDCD6."
FT /evidence="ECO:0000269|PubMed:19864416"
FT MUTAGEN 45
FT /note="L->A: Abolishes interaction with PDCD6."
FT /evidence="ECO:0000269|PubMed:19864416"
FT MUTAGEN 47..49
FT /note="YFF->AAA: Abolishes interaction with PDCD6."
FT /evidence="ECO:0000269|PubMed:19864416"
FT MUTAGEN 61..62
FT /note="RK->AA: Reduces PtdIns(3,5)P2 sensitivity."
FT /evidence="ECO:0000269|PubMed:22733759"
FT MUTAGEN 109
FT /note="Y->G: Abolishes formation and extrusion of tubulo-
FT vesicular structures and decreases lysosomal exocytosis
FT when overexpressed."
FT /evidence="ECO:0000269|PubMed:21256127"
FT MUTAGEN 110
FT /note="S->C: Modulates ion conduction; when associoated
FT with C-112 and C-113."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 111
FT /note="D->Q: Modulates inhibition by Ca(2+) at different pH
FT levels but does not abolish channel inward rectification;
FT when associated with Q-114 and Q-115."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 112
FT /note="G->C: Modulates ion conduction; when associoated
FT with C-110 and C-113."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 113
FT /note="A->C: Modulates ion conduction; when associoated
FT with C-110 and C-112."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 114
FT /note="D->Q: Modulates inhibition by Ca(2+) at different pH
FT levels but does not abolish channel inward rectification;
FT when associated with Q-111 and Q-115."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 115
FT /note="D->Q: Modulates inhibition by Ca(2+) at different pH
FT levels but does not abolish channel inward rectification;
FT when associated with Q-111 and Q-114."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 144
FT /note="L->K: Disrupts tetrameric assembly and abolishes
FT lysosomal localization; when associated with S-146."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 146
FT /note="R->S: Disrupts tetrameric assembly and abolishes
FT lysosomal localization; when associated with K-144."
FT /evidence="ECO:0000269|PubMed:28112729"
FT MUTAGEN 200
FT /note="R->H: Does not prevent proteolytic cleavage but
FT changes cleavage pattern."
FT /evidence="ECO:0000269|PubMed:16257972"
FT MUTAGEN 432
FT /note="V->P: Mediates localization to the plasma membrane
FT and strong inwardly rectifying current."
FT /evidence="ECO:0000269|PubMed:18794901,
FT ECO:0000269|PubMed:28112729"
FT MUTAGEN 471
FT /note="D->A: Fails to rescue defect of lactosylceramide
FT traffic through the late endocytic pathway in ML4 patient
FT cells."
FT /evidence="ECO:0000269|PubMed:16978393"
FT MUTAGEN 565..567
FT /note="CCC->AAA: Abolishes association with membranes."
FT /evidence="ECO:0000269|PubMed:16497227"
FT MUTAGEN 577..578
FT /note="LL->AA: No effect on localization to lysosomes."
FT /evidence="ECO:0000269|PubMed:16497227"
FT MUTAGEN 577
FT /note="L->A: Abolishes localization to lysosomes and leads
FT to expression at the cell membrane; when associated with A-
FT 15."
FT /evidence="ECO:0000269|PubMed:16497227,
FT ECO:0000269|PubMed:29019983"
FT CONFLICT 164..191
FT /note="ALCQRYYHRGHVDPANDTFDIDPMVVTD -> LSASGTTTEATWTRPTTHLT
FT LIRWWLLVN (in Ref. 3; AAG42242)"
FT /evidence="ECO:0000305"
FT CONFLICT 203
FT /note="P -> S (in Ref. 1; CAC08215)"
FT /evidence="ECO:0000305"
FT HELIX 41..49
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 52..58
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 84..105
FT /evidence="ECO:0007829|PDB:5TJA"
FT TURN 114..116
FT /evidence="ECO:0007829|PDB:5TJA"
FT HELIX 122..137
FT /evidence="ECO:0007829|PDB:5TJA"
FT HELIX 139..142
FT /evidence="ECO:0007829|PDB:5TJA"
FT STRAND 143..145
FT /evidence="ECO:0007829|PDB:5WJ9"
FT STRAND 148..151
FT /evidence="ECO:0007829|PDB:5TJB"
FT STRAND 154..156
FT /evidence="ECO:0007829|PDB:5TJA"
FT STRAND 162..176
FT /evidence="ECO:0007829|PDB:5TJA"
FT HELIX 177..179
FT /evidence="ECO:0007829|PDB:5TJA"
FT STRAND 181..195
FT /evidence="ECO:0007829|PDB:5TJA"
FT HELIX 218..220
FT /evidence="ECO:0007829|PDB:5WJ9"
FT HELIX 225..227
FT /evidence="ECO:0007829|PDB:5TJA"
FT STRAND 228..241
FT /evidence="ECO:0007829|PDB:5TJA"
FT HELIX 242..247
FT /evidence="ECO:0007829|PDB:5TJA"
FT STRAND 252..263
FT /evidence="ECO:0007829|PDB:5TJA"
FT STRAND 271..282
FT /evidence="ECO:0007829|PDB:5TJA"
FT HELIX 291..293
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 295..337
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 346..349
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 353..377
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 383..399
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 402..405
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 409..447
FT /evidence="ECO:0007829|PDB:7MGL"
FT TURN 448..450
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 452..454
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 457..467
FT /evidence="ECO:0007829|PDB:7MGL"
FT TURN 468..470
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 473..481
FT /evidence="ECO:0007829|PDB:7MGL"
FT TURN 482..486
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 488..507
FT /evidence="ECO:0007829|PDB:7MGL"
FT HELIX 510..524
FT /evidence="ECO:0007829|PDB:7MGL"
SQ SEQUENCE 580 AA; 65022 MW; 7E7691F58D01C804 CRC64;
MTAPAGPRGS ETERLLTPNP GYGTQAGPSP APPTPPEEED LRRRLKYFFM SPCDKFRAKG
RKPCKLMLQV VKILVVTVQL ILFGLSNQLA VTFREENTIA FRHLFLLGYS DGADDTFAAY
TREQLYQAIF HAVDQYLALP DVSLGRYAYV RGGGDPWTNG SGLALCQRYY HRGHVDPAND
TFDIDPMVVT DCIQVDPPER PPPPPSDDLT LLESSSSYKN LTLKFHKLVN VTIHFRLKTI
NLQSLINNEI PDCYTFSVLI TFDNKAHSGR IPISLETQAH IQECKHPSVF QHGDNSFRLL
FDVVVILTCS LSFLLCARSL LRGFLLQNEF VGFMWRQRGR VISLWERLEF VNGWYILLVT
SDVLTISGTI MKIGIEAKNL ASYDVCSILL GTSTLLVWVG VIRYLTFFHN YNILIATLRV
ALPSVMRFCC CVAVIYLGYC FCGWIVLGPY HVKFRSLSMV SECLFSLING DDMFVTFAAM
QAQQGRSSLV WLFSQLYLYS FISLFIYMVL SLFIALITGA YDTIKHPGGA GAEESELQAY
IAQCQDSPTS GKFRRGSGSA CSLLCCCGRD PSEEHSLLVN
