PKHM1_MOUSE
ID PKHM1_MOUSE Reviewed; 1074 AA.
AC Q7TSI1; Q3U3L2; Q8CHU5;
DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2003, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Pleckstrin homology domain-containing family M member 1 {ECO:0000305};
DE Short=PH domain-containing family M member 1;
GN Name=Plekhm1 {ECO:0000312|MGI:MGI:2443207};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=NOD;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Brain, and Kidney;
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-218; SER-436 AND SER-491, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP INTERACTION WITH PAFAH1B1.
RX PubMed=22073305; DOI=10.1371/journal.pone.0027285;
RA Ye S., Fowler T.W., Pavlos N.J., Ng P.Y., Liang K., Feng Y., Zheng M.,
RA Kurten R., Manolagas S.C., Zhao H.;
RT "LIS1 regulates osteoclast formation and function through its interactions
RT with dynein/dynactin and Plekhm1.";
RL PLoS ONE 6:E27285-E27285(2011).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=25498145; DOI=10.1016/j.molcel.2014.11.006;
RA McEwan D.G., Popovic D., Gubas A., Terawaki S., Suzuki H., Stadel D.,
RA Coxon F.P., Miranda de Stegmann D., Bhogaraju S., Maddi K., Kirchof A.,
RA Gatti E., Helfrich M.H., Wakatsuki S., Behrends C., Pierre P., Dikic I.;
RT "PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and
RT LC3/GABARAP proteins.";
RL Mol. Cell 57:39-54(2015).
RN [7]
RP FUNCTION, INTERACTION WITH DEF8; FAM98A; NDEL1 AND RAB7A, DISRUPTION
RP PHENOTYPE, AND MUTAGENESIS OF ARG-714 AND 949-TYR-LEU-950.
RX PubMed=27777970; DOI=10.1172/jci.insight.86330;
RA Fujiwara T., Ye S., Castro-Gomes T., Winchell C.G., Andrews N.W.,
RA Voth D.E., Varughese K.I., Mackintosh S.G., Feng Y., Pavlos N.,
RA Nakamura T., Manolagas S.C., Zhao H.;
RT "PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone
RT homeostasis.";
RL JCI Insight 1:E86330-E86330(2016).
CC -!- FUNCTION: Acts as a multivalent adapter protein that regulates Rab7-
CC dependent and HOPS complex-dependent fusion events in the endolysosomal
CC system and couples autophagic and the endocytic trafficking pathways.
CC Acts as a dual effector of RAB7A and ARL8B that simultaneously binds
CC these GTPases, bringing about clustering and fusion of late endosomes
CC and lysosomes. Required for late stages of endolysosomal maturation,
CC facilitating both endocytosis-mediated degradation of growth factor
CC receptors and autophagosome clearance. Interaction with Arl8b is a
CC crucial factor in the terminal maturation of autophagosomes and to
CC mediate autophagosome-lysosome fusion (PubMed:25498145). Positively
CC regulates lysosome peripheral distribution and ruffled border formation
CC in osteoclasts (PubMed:27777970). May be involved in negative
CC regulation of endocytic transport from early endosome to late
CC endosome/lysosome implicating its association with Rab7. May have a
CC role in sialyl-lex-mediated transduction of apoptotic signals (By
CC similarity). Involved in bone resorption (PubMed:27777970).
CC {ECO:0000250|UniProtKB:Q9Y4G2, ECO:0000269|PubMed:25498145,
CC ECO:0000269|PubMed:27777970}.
CC -!- SUBUNIT: Interacts (via N- and C-terminus) with RAB7A (GTP-bound form).
CC Simultaneously interacts with RAB7A and ARL8B; bringing about
CC clustering and fusion of late endosomes and lysosomes. Interacts (via
CC RUN domain) with ARL8B (GTP-bound form); the interaction is required
CC for PLEKHM1 localization to lysosomes and for ARL8B function in
CC delivery and degradation of endocytic and autophagic cargo in
CC lysosomes. PLEKHM1 and PLEKHM2 compete for interaction with ARL8B.
CC Interacts with ARL8A; the interaction is weaker than with ARL8B.
CC Interacts with VPS41, VPS11, VPS18, VPS33A and VPS39; indicative for an
CC association with the HOPS complex; the interactions with, at least,
CC VPS41, VPS11, VPS18 and VPS33A require ARL8B (By similarity). Interacts
CC with GABARAP, GABARAPL, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C (By
CC similarity). Interacts with PAFAH1B (PubMed:22073305). Interacts (via
CC N- and C-terminus) with NDEL1 (PubMed:27777970). Interacts (via C-
CC terminus) with MAP3K7 (PubMed:27777970). Interacts (via N- and C-
CC terminus) with FAM98A (PubMed:27777970). Interacts (via C-terminus)
CC with DEF8; this interaction is weak but increased in a RAB7A-dependent
CC manner (PubMed:27777970). May interact with sialyl-lex-positive protein
CC (By similarity). {ECO:0000250|UniProtKB:Q9Y4G2,
CC ECO:0000269|PubMed:22073305, ECO:0000269|PubMed:27777970}.
CC -!- SUBCELLULAR LOCATION: Autolysosome membrane
CC {ECO:0000250|UniProtKB:Q9Y4G2}. Endosome membrane
CC {ECO:0000250|UniProtKB:Q9Y4G2}. Late endosome membrane
CC {ECO:0000250|UniProtKB:Q9Y4G2}. Lysosome membrane
CC {ECO:0000250|UniProtKB:Q9Y4G2}. Note=In case of infection colocalizes
CC with Salmonella typhimurium sifA in proximity of Salmonella-containing
CC vacuole (SCV). {ECO:0000250|UniProtKB:Q9Y4G2}.
CC -!- DOMAIN: The LIR (LC3-interacting region) motif mediates the interaction
CC with ATG8 family proteins GABARAP, GABARAPL, GABARAPL2, and LC3A/B/C.
CC {ECO:0000250|UniProtKB:Q9Y4G2}.
CC -!- DISRUPTION PHENOTYPE: Osteoclast-specific conditional knockout mice
CC show normal tooth eruption, developed normally and are fertile, but
CC trabecular bone mass in long bones and vertebrae is increased
CC (PubMed:27777970). Osteoclast differentiation and number are normal,
CC but bone resorption is decreased (PubMed:27777970). Show
CC mislocalization of osteoclast lysosomes at the perinuclear area,
CC instead at the cell periphery, and decreased ruffled border formation
CC (PubMed:27777970). {ECO:0000269|PubMed:27777970}.
CC -!- MISCELLANEOUS: Sialyl-lex is a carcinoma associated antigen.
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DR EMBL; AK154703; BAE32773.1; -; mRNA.
DR EMBL; AL772325; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL929552; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC038943; AAH38943.1; -; mRNA.
DR EMBL; BC053079; AAH53079.1; -; mRNA.
DR CCDS; CCDS25518.1; -.
DR RefSeq; NP_898855.1; NM_183034.1.
DR AlphaFoldDB; Q7TSI1; -.
DR SMR; Q7TSI1; -.
DR BioGRID; 237251; 1.
DR IntAct; Q7TSI1; 1.
DR STRING; 10090.ENSMUSP00000047327; -.
DR iPTMnet; Q7TSI1; -.
DR PhosphoSitePlus; Q7TSI1; -.
DR EPD; Q7TSI1; -.
DR jPOST; Q7TSI1; -.
DR MaxQB; Q7TSI1; -.
DR PaxDb; Q7TSI1; -.
DR PeptideAtlas; Q7TSI1; -.
DR PRIDE; Q7TSI1; -.
DR ProteomicsDB; 289911; -.
DR Antibodypedia; 30012; 146 antibodies from 27 providers.
DR Ensembl; ENSMUST00000041272; ENSMUSP00000047327; ENSMUSG00000034247.
DR GeneID; 353047; -.
DR KEGG; mmu:353047; -.
DR UCSC; uc007lug.1; mouse.
DR CTD; 9842; -.
DR MGI; MGI:2443207; Plekhm1.
DR VEuPathDB; HostDB:ENSMUSG00000034247; -.
DR eggNOG; KOG1829; Eukaryota.
DR GeneTree; ENSGT00940000155111; -.
DR HOGENOM; CLU_011318_0_0_1; -.
DR InParanoid; Q7TSI1; -.
DR OMA; HVLNCDL; -.
DR OrthoDB; 177737at2759; -.
DR PhylomeDB; Q7TSI1; -.
DR TreeFam; TF317067; -.
DR BioGRID-ORCS; 353047; 3 hits in 71 CRISPR screens.
DR ChiTaRS; Plekhm1; mouse.
DR PRO; PR:Q7TSI1; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q7TSI1; protein.
DR Bgee; ENSMUSG00000034247; Expressed in granulocyte and 189 other tissues.
DR ExpressionAtlas; Q7TSI1; baseline and differential.
DR Genevisible; Q7TSI1; MM.
DR GO; GO:0044754; C:autolysosome; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0005730; C:nucleolus; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061909; P:autophagosome-lysosome fusion; ISS:UniProtKB.
DR GO; GO:1902774; P:late endosome to lysosome transport; ISS:UniProtKB.
DR GO; GO:0032418; P:lysosome localization; IMP:UniProtKB.
DR GO; GO:0045780; P:positive regulation of bone resorption; IMP:UniProtKB.
DR GO; GO:1900029; P:positive regulation of ruffle assembly; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR CDD; cd13321; PH_PLEKHM1; 1.
DR Gene3D; 1.20.58.900; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR002219; PE/DAG-bd.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR042827; PLEKHM1_PH.
DR InterPro; IPR004012; Run_dom.
DR InterPro; IPR037213; Run_dom_sf.
DR InterPro; IPR025258; Zf-RING_9.
DR Pfam; PF02759; RUN; 1.
DR Pfam; PF13901; zf-RING_9; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM01175; DUF4206; 1.
DR SMART; SM00233; PH; 2.
DR SMART; SM00593; RUN; 1.
DR SUPFAM; SSF140741; SSF140741; 1.
DR PROSITE; PS50003; PH_DOMAIN; 2.
DR PROSITE; PS50826; RUN; 1.
DR PROSITE; PS50081; ZF_DAG_PE_2; 1.
PE 1: Evidence at protein level;
KW Autophagy; Cytoplasmic vesicle; Endosome; Lysosome; Membrane;
KW Metal-binding; Phosphoprotein; Protein transport; Reference proteome;
KW Repeat; Transport; Zinc; Zinc-finger.
FT CHAIN 1..1074
FT /note="Pleckstrin homology domain-containing family M
FT member 1"
FT /id="PRO_0000309336"
FT DOMAIN 40..182
FT /note="RUN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00178"
FT DOMAIN 551..642
FT /note="PH 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 701..795
FT /note="PH 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT ZN_FING 1004..1058
FT /note="Phorbol-ester/DAG-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT REGION 214..244
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 272..336
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 382..454
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 506..526
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 661..680
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 672..1074
FT /note="Interaction with RAB7A"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G2"
FT MOTIF 649..655
FT /note="LIR"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G2"
FT COMPBIAS 309..336
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 382..408
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 511..525
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 218
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 433
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4G2"
FT MOD_RES 436
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 491
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 714
FT /note="R->C: No change in osteoclast formation and bone
FT resorption."
FT /evidence="ECO:0000269|PubMed:27777970"
FT MUTAGEN 949..950
FT /note="YL->AA: Decreases interaction with RAB7A."
FT /evidence="ECO:0000269|PubMed:27777970"
FT CONFLICT 742..744
FT /note="DSH -> TRP (in Ref. 3; AAH38943)"
FT /evidence="ECO:0000305"
FT CONFLICT 768
FT /note="T -> S (in Ref. 1; BAE32773)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1074 AA; 118535 MW; 56EDA05514E4B9F9 CRC64;
MLSVENGLDP RAAIQVIKKK LVGSVKALQK QHVSLDTVVT SEDGDANTMC SALEAVFIHG
LHAKHIRAEA GGKRKKHTHQ KALPQPVFWP LLKAITHRHI VSDLEHLVFI NTDVGRCRAW
LRLALNDGLM ECYLKLLLQE PARLCEYYQP TALLRDAEEA EFLLSFLQGL TSLSFELSYK
SAILNEWTLT PLSLSGLCPL SELDPLTTSG AELQRKESLD SISHSSGSED IEVQHSGHKI
RRNRKLTASS LSLDTASSSQ LSCSLNSDSC LLQENGPKSP DHSEEPMSYD SDLGMANTDD
PDRSLQEVLS EFSKAQVNSA PSSGPNQEPD TPMFQTPLSL HSLATSTHLH FEGSEELFPA
HKSSGTSSGG HKHQLLPQET PDEKQLGTAQ AGPAQSTSDQ QPSSPVGGAA GQGSGPWKAL
EYGRVGPKLV VSSPTSPKGK SWISEDDFCR PPQEPALKSA AGLCTSPVQD TPESRAALHG
PFSQGPRKSC SLGALDKACV PSQACGNAQP APAPAPAPAP APAPAPGVTQ DHKNFCVVHR
RQMGLSNPFR GLMKLGTVAR RGAMGIWKEF FCELSPLEFR LYLSDEERTC VESCSLLRCE
AVGPAHSDGR FELVFSGKKL ALRASSQDEA EDWLDRVREA LQKVRPQQED EWVNIQYPDQ
AEDAPEAPPD SLPPYSTLLP EPAGAQGMQL DWTSAQVPEP DAIKESLLYL YADRTWVPYI
FSLSLESLKC FRVRNNEKML SDSHGVETIR DILPDTSLGG PAFFKIITAK AVLKLQAKNT
EEATHWRDLV RKVLASYLES AEEAVTLGGS LDEKCQEVLK FATRENGFLL QYLVAIPTEK
GLDSQGCFCA GCSRQIGFSF VRPKLCAFSG LYYCDFCHQD DASVIPARII HNWDLTKRPV
CRQALKFLAQ IRAQPLINLQ LVNASLYEHV ERMHLIGRSR EQLKLLGDYL GLCRSGALKE
LCKRLSHRNY LLESPHRFSV ADLQQIAEGV YEGFLKALIE FASQHVYHCD LCTQRGFICQ
ICHHQDIIFP FEFDTTVRCA ECRTVFHQSC QAVVRKGCPR CARRRKYQEQ NVVS
