MTMR6_RAT
ID MTMR6_RAT Reviewed; 655 AA.
AC A0A0G2JXT6;
DT 13-FEB-2019, integrated into UniProtKB/Swiss-Prot.
DT 22-JUL-2015, sequence version 1.
DT 03-AUG-2022, entry version 44.
DE RecName: Full=Myotubularin-related protein 6 {ECO:0000305};
DE AltName: Full=Phosphatidylinositol-3,5-bisphosphate 3-phosphatase {ECO:0000305};
DE EC=3.1.3.95 {ECO:0000250|UniProtKB:Q9Y217};
DE AltName: Full=Phosphatidylinositol-3-phosphate phosphatase {ECO:0000305};
DE EC=3.1.3.64 {ECO:0000250|UniProtKB:Q9Y217};
GN Name=Mtmr6 {ECO:0000312|RGD:1305378};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116 {ECO:0000312|Proteomes:UP000002494};
RN [1] {ECO:0000312|Proteomes:UP000002494}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway {ECO:0000312|Proteomes:UP000002494};
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2] {ECO:0007744|PubMed:22673903}
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [3] {ECO:0000305}
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23188820; DOI=10.1074/jbc.m112.395087;
RA Mochizuki Y., Ohashi R., Kawamura T., Iwanari H., Kodama T., Naito M.,
RA Hamakubo T.;
RT "Phosphatidylinositol 3-phosphatase myotubularin-related protein 6 (MTMR6)
RT is regulated by small GTPase Rab1B in the early secretory and autophagic
RT pathways.";
RL J. Biol. Chem. 288:1009-1021(2013).
CC -!- FUNCTION: Phosphatase that acts on lipids with a phosphoinositol
CC headgroup. Dephosphorylates phosphatidylinositol 3-phosphate
CC (PtdIns(3)P) and phosphatidylinositol 3,5-bisphosphate. Binds with high
CC affinity to phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) but
CC also to phosphatidylinositol 3-phosphate (PtdIns(3)P),
CC phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol
CC 5-phosphate (PtdIns(5)P), phosphatidic acid and phosphatidylserine (By
CC similarity). Negatively regulates ER-Golgi protein transport
CC (PubMed:23188820). Probably in association with MTMR9, plays a role in
CC the late stages of macropinocytosis by dephosphorylating
CC phosphatidylinositol 3-phosphate in membrane ruffles. Acts as a
CC negative regulator of KCNN4/KCa3.1 channel activity in CD4(+) T-cells
CC possibly by decreasing intracellular levels of phosphatidylinositol 3-
CC phosphate. Negatively regulates proliferation of reactivated CD4(+) T-
CC cells. In complex with MTMR9, negatively regulates DNA damage-induced
CC apoptosis. The formation of the MTMR6-MTMR9 complex stabilizes both
CC MTMR6 and MTMR9 protein levels (By similarity).
CC {ECO:0000250|UniProtKB:Q9Y217, ECO:0000269|PubMed:23188820}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-
CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-5-phosphate) + phosphate; Xref=Rhea:RHEA:39019,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57795,
CC ChEBI:CHEBI:57923; EC=3.1.3.95;
CC Evidence={ECO:0000250|UniProtKB:Q9Y217};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-
CC phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol) + phosphate; Xref=Rhea:RHEA:12316, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57880, ChEBI:CHEBI:58088; EC=3.1.3.64;
CC Evidence={ECO:0000250|UniProtKB:Q9Y217};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-
CC bisphosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-5-phosphate) + phosphate; Xref=Rhea:RHEA:45632,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:78911,
CC ChEBI:CHEBI:85342; Evidence={ECO:0000250|UniProtKB:Q9Y217};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dioctanoyl-sn-glycero-3-phospho-(1-D-myo-inositol-3-
CC phosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-
CC inositol) + phosphate; Xref=Rhea:RHEA:42328, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:65221, ChEBI:CHEBI:78934;
CC Evidence={ECO:0000250|UniProtKB:Q9Y217};
CC -!- ACTIVITY REGULATION: Allosterically activated by phosphatidylserine
CC and/or phosphatidylinositol 4-phosphate (PtdIns(4)P), and
CC phosphatidylinositol 5-phosphate (PtdIns(5)P) (By similarity).
CC Interaction with MTMR9 increases catalytic activity towards
CC phosphatidylinositol 3,5-bisphosphate (By similarity).
CC {ECO:0000250|UniProtKB:Q9Y217}.
CC -!- SUBUNIT: Homodimer. Heterodimer (via C-terminus) with MTMR9 (via C-
CC terminus). Interacts with ALKBH4. Interacts with KCNN4. Interacts (via
CC GRAM domain) with RAB1B (in GDP-bound form); the interaction regulates
CC MTMR6 recruitment to the endoplasmic reticulum-Golgi intermediate
CC compartment. {ECO:0000250|UniProtKB:Q9Y217}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23188820}.
CC Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9Y217}. Cell projection,
CC ruffle membrane {ECO:0000250|UniProtKB:Q8VE11}; Peripheral membrane
CC protein {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Endoplasmic
CC reticulum-Golgi intermediate compartment {ECO:0000269|PubMed:23188820}.
CC Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:Q9Y217}.
CC Note=Localizes to ruffles during EGF-induced macropinocytosis (By
CC similarity). Colocalizes with MTMR9 to the perinuclear region (By
CC similarity). Partially localizes to the endoplasmic reticulum (By
CC similarity). Co-localizes with RAB1B to the endoplasmic reticulum-Golgi
CC intermediate compartment and to the peri-Golgi region
CC (PubMed:23188820). {ECO:0000250|UniProtKB:Q8VE11,
CC ECO:0000250|UniProtKB:Q9Y217, ECO:0000269|PubMed:23188820}.
CC -!- DOMAIN: The GRAM domain is required for cell membrane localization.
CC {ECO:0000250|UniProtKB:Q8VE11}.
CC -!- DOMAIN: The C-terminus domain (aa 540-655) mediates interaction with
CC MTMR9. {ECO:0000250|UniProtKB:Q8VE11}.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family. Non-
CC receptor class myotubularin subfamily. {ECO:0000255}.
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DR EMBL; AABR07018115; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; XP_006252173.1; XM_006252111.2.
DR AlphaFoldDB; A0A0G2JXT6; -.
DR SMR; A0A0G2JXT6; -.
DR jPOST; A0A0G2JXT6; -.
DR Ensembl; ENSRNOT00000082665; ENSRNOP00000070397; ENSRNOG00000012918.
DR GeneID; 305935; -.
DR CTD; 9107; -.
DR RGD; 1305378; Mtmr6.
DR GeneTree; ENSGT00940000158055; -.
DR OMA; PNTDYMY; -.
DR OrthoDB; 824298at2759; -.
DR Reactome; R-RNO-1660499; Synthesis of PIPs at the plasma membrane.
DR PRO; PR:A0A0G2JXT6; -.
DR Proteomes; UP000002494; Chromosome 15.
DR Bgee; ENSRNOG00000012918; Expressed in adult mammalian kidney and 19 other tissues.
DR ExpressionAtlas; A0A0G2JXT6; baseline and differential.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR GO; GO:0005635; C:nuclear envelope; ISO:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0052629; F:phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0106018; F:phosphatidylinositol-3,5-bisphosphate phosphatase activity; ISO:RGD.
DR GO; GO:0004438; F:phosphatidylinositol-3-phosphatase activity; ISO:RGD.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; ISO:RGD.
DR CDD; cd13343; PH-GRAM_MTMR6; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR030581; MTMR6.
DR InterPro; IPR035998; MTMR6_PH-GRAM.
DR InterPro; IPR010569; Myotubularin-like_Pase_dom.
DR InterPro; IPR030564; Myotubularin_fam.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR029021; Prot-tyrosine_phosphatase-like.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR003595; Tyr_Pase_cat.
DR PANTHER; PTHR10807; PTHR10807; 1.
DR PANTHER; PTHR10807:SF34; PTHR10807:SF34; 1.
DR Pfam; PF06602; Myotub-related; 1.
DR SMART; SM00404; PTPc_motif; 1.
DR SUPFAM; SSF52799; SSF52799; 2.
DR PROSITE; PS51339; PPASE_MYOTUBULARIN; 1.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Coiled coil; Cytoplasm; Endocytosis;
KW Endoplasmic reticulum; Hydrolase; Lipid metabolism; Membrane;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..655
FT /note="Myotubularin-related protein 6"
FT /id="PRO_0000446364"
FT DOMAIN 1..101
FT /note="GRAM"
FT /evidence="ECO:0000255"
FT DOMAIN 124..537
FT /note="Myotubularin phosphatase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00669"
FT REGION 2..141
FT /note="Interaction with RAB1B"
FT /evidence="ECO:0000250|UniProtKB:Q8VE11"
FT COILED 547..581
FT /evidence="ECO:0000255"
FT ACT_SITE 374
FT /note="Phosphocysteine intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10044"
FT BINDING 286..289
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q13614"
FT BINDING 311..312
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q13614"
FT BINDING 374..380
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q13614"
FT BINDING 420
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q13614"
FT MOD_RES 108
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q8VE11"
FT MOD_RES 595
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y217"
FT MOD_RES 623
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y217"
FT MOD_RES 645
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y217"
SQ SEQUENCE 655 AA; 75577 MW; CFACCB08BFF8CC4C CRC64;
MEHIRTTKVE QVKLLDRFST NNKSLTGTLY LTATHLLFID AHQKETWILH HHIASVEKLA
LTTSGCPLVI QCKNFRIVHF IVPRERDCHD IYNSLLQLSK QAKYEDLYAF SYNPKQNDTE
RLNGWQLIDL AAEYERMGVP NANWQLSDAN REYKVCETYP RELYVPRTAS RPVIVGSSNF
RSKGRLPVLS YCQQGTEAAI CRCSQPLSGF SARCLEDEHL LQAISKANPG NRYMYVVDTR
PKLRMQSWWD TQKDIGRIIV RISSKIWNDE KIRESDEKKR LNAMANRAAG KGYENEDNYS
NIRFQFVGIE NIHVMRSSLQ KLLEVNGSKG LSVNDFYSGL ESSGWLRHIK AVLDAAIFLA
KAIVVENASV LVHCSDGWDR TSQVCSLGSL LLDSYYRTMK GFMVLIEKDW ISFGHKFSER
CGHLDGDPKE VSPVFTQFLE CVWHLTEQFP QAFEFNEAFL LQIHEHIHSC QFGNFLGNCQ
KEREELRLKE KTYSLWPFLL ADKKKYLNPL YSSKSQRLTV LEPNTASFNF KFWRNMYHQF
DRTLHPRQSV LNIIMNMNEQ NKQLEEDVKD LEAKIKQCKS GILTKDLLHA VHPESPSLKT
SLCLKEQSLL PVKDTLRAVE GSSPADNRYC DYTEEFSKSE PAVVSLEYGV ARMTC
