MTMR9 (myotubularin-related protein 9) is a catalytically inactive member of the myotubularin family of phosphoinositide 3-phosphatases. The horse protein encoded by this full-length 549-residue product has the family architecture: an N-terminal PH-GRAM domain, a myotubularin phosphatase-like domain in which the catalytic cysteine and arginine of the HCX5R active-site loop are replaced, and a C-terminal coiled coil that mediates dimerization. In mammals MTMR9 is a non-catalytic regulatory partner of the active myotubularins MTMR6, MTMR7 and MTMR8: it forms heterodimers with them through the coiled coil, stabilizes the active partner, raises its catalytic rate and shapes its substrate preference (MTMR6-MTMR9 favours phosphatidylinositol 3,5-bisphosphate, MTMR8-MTMR9 favours phosphatidylinositol 3-phosphate). It is a soluble cytoplasmic protein that associates with intracellular membranes, the perinuclear region and membrane ruffles. These activities have been shown for human and mouse MTMR9; the horse protein, which is 98% identical to human MTMR9 over its full length with an identical active-site loop and coiled coil, is expected to share them but has not been studied directly.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, mapped from an ARBA-derived subcellular-location line on the horse record. Human MTMR9 partially localizes to the ER. Reason: The horse record's location line is an ARBA prediction, but the claim is independently supported by the experimental human observation that MTMR9 partially localizes to the ER (PMID:19038970, recorded in human UniProt as ECO:0000269). The horse protein is a full-length, 98%-identical member of the same PANTHER subfamily (PTHR10807:SF56), so the location is a reasonable transfer. It is partial and not the main site of the partner-phosphatase regulatory function, so it is non-core. No horse experiment exists. Supporting Evidence: file:human/MTMR9/MTMR9-uniprot.txt Endoplasmic reticulum {ECO:0000269|PubMed:19038970} file:HORSE/MTMR9__A0A5F5PR89/MTMR9__A0A5F5PR89-uniprot.txt DR PANTHER; PTHR10807:SF56; MYOTUBULARIN-RELATED PROTEIN 9; 1. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: Cytosol, from an ARBA rule. MTMR9 is a soluble cytoplasmic protein. Reason: Human MTMR9 is experimentally cytoplasmic (PMID:16787938, PMID:19038970), and PAINT propagated cytoplasm (GO:0005737) from a deep node (PTN000743854) seeded by many family members including human MTMR9. The horse product has no transmembrane segment or signal peptide and is 98% identical to the human protein, so a soluble cytosolic pool that engages the partner phosphatases at the cytosolic face of membranes is well grounded. The supporting evidence is the human experimental data and the PAINT node, not the ARBA rule itself; no horse experiment exists. Supporting Evidence: file:human/MTMR9/MTMR9-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16787938, PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells |
| GO:0030234 enzyme regulator activity | IEA GO_REF:0000117 | MODIFY | Summary: Electronic enzyme regulator activity; correct but general. Reason: True but less specific than the evidence supports. MTMR9 lacks the catalytic cysteine and arginine of the myotubularin active-site loop (identical HGTEGTDST loop in horse and human), and in human and mouse it binds the active lipid phosphatases MTMR6, MTMR7 and MTMR8 and raises their catalytic activity. The precise descendant is phosphatase activator activity (GO:0019211), the term human MTMR9 carries by experiment. The transfer to horse rests on full-length 98% identity, membership of the same PANTHER subfamily (PTHR10807:SF56) and a 100%-identical partner-binding coiled coil; it is not shown in horse. Proposed replacements: phosphatase activator activity Supporting Evidence: PMID:19038970 MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity file:HORSE/MTMR9__A0A5F5PR89/MTMR9__A0A5F5PR89-bioinformatics/RESULTS.md HCX5R active-site loop (human 332-340): human `HGTEGTDST`, horse `HGTEGTDST` |
| GO:0032587 ruffle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Ruffle membrane, mapped from an ARBA-derived subcellular-location line. Mammalian MTMR9 localizes to ruffles during EGF-induced macropinocytosis. Reason: The ruffle location of mammalian MTMR9 rests on the mouse ortholog Q9Z2D0 (transferred to human UniProt as ECO:0000250), and MTMR6 and MTMR9 are required for late macropinocytosis (PMID:24591580). The horse protein retains the PH-GRAM domain (97.9% identical to human), which in mouse is required for membrane localization. This is a stimulus-dependent location, not the principal site of function, so it is kept as non-core. No horse experiment exists. Supporting Evidence: file:human/MTMR9/MTMR9-uniprot.txt Localizes to ruffles during EGF-induced macropinocytosis (By similarity) PMID:24591580 its binding partner MTMR9, are required for macropinocytosis file:HORSE/MTMR9__A0A5F5PR89/MTMR9__A0A5F5PR89-bioinformatics/RESULTS.md PH-GRAM (human 4-99): 97.9% identity |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Perinuclear region, mapped from an ARBA-derived subcellular-location line. Human MTMR9 colocalizes with MTMR6 in the perinuclear region. Reason: Supported by the experimental human observation (PMID:16787938, PMID:19038970, ECO:0000269 in human UniProt) and transferable to the 98%-identical horse protein in the same PANTHER subfamily. It is a descriptive sub-location of the cytoplasmic pool rather than a defining site of function. No horse experiment exists. Supporting Evidence: file:human/MTMR9/MTMR9-uniprot.txt Colocalizes with MTMR6 to the perinuclear region (PubMed:19038970) |
| GO:0019902 phosphatase binding | ISS PMID:19038970 MTMR9 increases MTMR6 enzyme activity, stability, and role i... | NEW | Summary: Proposed. MTMR9 heterodimerizes with the active lipid phosphatases MTMR6, MTMR7 and MTMR8 through its C-terminal coiled coil. Reason: Binding to the active myotubularin phosphatases is the physical basis of MTMR9 function and is shown for human MTMR9 with MTMR6 and MTMR8 (PMID:19038970, PMID:16787938, PMID:22647598) and for mouse Mtmr9 with Mtmr7 (PMID:12890864). The partners are lipid phosphatases, so the general phosphatase binding term is used rather than protein phosphatase binding (GO:0019903); this follows the human review. PAINT placed the related protein phosphatase binding term at the MTMR9 node PTN002246859 (seeded by human MTMR9), which establishes the function as inherited across the MTMR9 clade, and the horse gene's tree member F7CCR9 receives that IBA. A0A5F5PR89 is not itself in the PANTHER tree, but it is the full-length product of the same gene, maps to PTHR10807:SF56, and its coiled coil (human 508-542) is 100% identical to human. Not shown experimentally in horse. Supporting Evidence: PMID:19038970 human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells PMID:16787938 identified novel heteromeric interactions: MTMR8 with MTMR9 file:HORSE/MTMR9__A0A5F5PR89/MTMR9__A0A5F5PR89-bioinformatics/RESULTS.md C-terminal coiled coil (human 508-542): 100.0% identity |
| GO:0060304 regulation of phosphatidylinositol dephosphorylation | ISS PMID:22647598 Myotubularin-related protein (MTMR) 9 determines the enzymat... | NEW | Summary: Proposed. MTMR9 regulates 3-phosphoinositide dephosphorylation by activating, and setting the substrate preference of, its partner phosphatases MTMR6 and MTMR8. Reason: MTMR9 does part of the work of this process directly, as the activating subunit of the partner phosphatase rather than as a substrate or a requirement upstream. In human cells and with purified components the MTMR8-MTMR9 and MTMR6-MTMR9 complexes have higher activity and altered substrate preference, and MTMR8-MTMR9 lowers cellular PI3P (PMID:22647598, PMID:19038970); human MTMR9 carries this term by IDA. Transferred to the horse full-length product on the basis of the same PANTHER subfamily (PTHR10807:SF56), 98% identity and an identical coiled coil. Not shown in horse. Supporting Evidence: PMID:22647598 Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity PMID:22647598 the MTMR8/R9 complex reduces cellular PtdIns(3)P levels |
| GO:0050821 protein stabilization | ISS PMID:19038970 MTMR9 increases MTMR6 enzyme activity, stability, and role i... | NEW | Summary: Proposed. Heterodimer formation with MTMR9 raises the protein levels of its partner phosphatases. Reason: MTMR9 stabilizes MTMR6 and MTMR8 by binding them directly (PMID:19038970; PMID:22647598 per human UniProt); human MTMR9 carries this term by IDA. The stabilization is mediated by the heterodimer, whose MTMR9 interface (the C-terminal coiled coil) is 100% identical in the horse product. Not shown in horse. Supporting Evidence: PMID:19038970 the formation of this heteromer in cells resulted in increased protein levels of both MTMR6 and MTMR9 file:human/MTMR9/MTMR9-uniprot.txt Stabilizes MTMR8 protein levels (PubMed:22647598) |
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Download this section (compressed HTML)Q: Is A0A5F5PR89 (ENSECAT00000074905, full-length, 549 aa) or F7CCR9 (Ensembl canonical, with a divergent last exon that truncates the coiled coil) the predominant horse MTMR9 transcript in tissues, and should the PANTHER tree member for horse be switched to the full-length product?
Q: Does horse MTMR9 heterodimerize with and activate horse MTMR6 and MTMR8 with the same substrate preferences reported for the human complexes?
Experiment: Co-express horse MTMR9 (A0A5F5PR89) with horse MTMR6 or MTMR8, test co-immunoprecipitation and measure 3-phosphatase activity of the purified complexes on PI3P and PI(3,5)P2 relative to the active partner alone.
Type: biochemical reconstitution
Experiment: RNA-seq or RT-PCR across horse tissues to quantify the relative usage of the full-length MTMR9 terminal exon versus the divergent F7CCR9 terminal exon.
Type: transcript analysis
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Download this section (compressed HTML)Script: compare_to_human.py (global pairwise alignment, Biopython). Output: results.json.
HGTEGTDST, horse HGTEGTDSTLoading supporting content…
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