Mtmr12

UniProt ID: A0A8I5ZMD5
Organism: Rattus norvegicus
Review Status: COMPLETE
πŸ“ Provide Detailed Feedback

Gene Description

Myotubularin-related protein 12 (MTMR12, also called 3-phosphatase adapter protein, 3-PAP) is a catalytically inactive member of the myotubularin family. Its myotubularin-like phosphatase fold lacks the catalytic cysteine and arginine of the CX5R motif, so it has no intrinsic phosphoinositide 3-phosphatase activity. It acts as a noncatalytic partner of the active lipid phosphatase MTM1 (myotubularin), binding it directly, holding it in the cytoplasm and maintaining its protein abundance; it also associates with MTMR2. In skeletal muscle the MTM1-MTMR12 complex sits at triads, where the sarcoplasmic reticulum meets the T-tubules, and loss of MTMR12 destabilizes MTM1 and disorganizes triads and myofibres. The rat UniProt entry A0A8I5ZMD5 is an Ensembl alternative gene model of Mtmr12 whose first 40 residues replace the conserved canonical N-terminus (residues 1-56 of Q5FVM6); the rest of the protein, including the whole pseudophosphatase domain, is identical to the canonical rat product.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0016529 sarcoplasmic reticulum
IEA
GO_REF:0000044 		ACCEPT
Summary: MTMR12 localizes with MTM1 at skeletal-muscle triads and partly overlaps the sarcoplasmic-reticulum marker RyR1 in mouse muscle (the basis of the mouse EXP annotation to this term). The localization is a gene-level property of the MTM1-MTMR12 complex.
Reason: The claim is about the Mtmr12 gene product and is directly supported in mouse muscle (PMID:23818870), an ortholog in the same PANTHER subfamily (PTHR10807:SF37). The mouse ortholog carries an EXP annotation to this term from that paper, and the canonical rat product Q5FVM6 receives it by ISO. The earlier UNDECIDED rested on the predicted signal peptide of this product's alternative N-terminus. That segment is absent from the cDNA-supported rat, mouse and human products (RESULTS-rereview.md) and is most likely a gene-model feature; even if it were translated and used, ER/SR import would not move the protein out of the sarcoplasmic reticulum. ACCEPT, with the triad localization being the functionally relevant location.
Supporting Evidence:
PMID:23818870
co-localization of MTMR12 was observed with ryanodine receptors, a sarcoplasmic reticulum marker
PMID:23818870
The expression of MTMR12 was restricted to triads as no co-localization was observed with Ξ±-actinin at Z-lines
file:rat/Mtmr12/Mtmr12-bioinformatics/RESULTS-rereview.md
A0A8I5ZMD5 residues 41-732 align to Q5FVM6 residues 57-748 with 691 identical residues (691/692).
GO:0030017 sarcomere
IEA
GO_REF:0000044 		MODIFY
Summary: MTMR12 shows a striated pattern in muscle, but the primary report places it at triads and explicitly not at alpha-actinin-positive Z-lines. GO sarcomere is defined by the array of thick and thin filaments between Z discs, which is not where MTMR12 was found.
Reason: The SubCell mapping turns a striated triad pattern into sarcomere. The experimental basis (mouse tibialis anterior, PMID:23818870) says MTMR12 is restricted to triads; mouse MGI curators annotated sarcoplasmic reticulum from this paper, not sarcomere. The correct lateral replacement is GO:0030314 junctional membrane complex (the triad: the junction of SR and T-tubule membranes). This is a lateral correction rather than a refinement, because the junctional membrane complex is not part of the sarcomere in GO. Confocal co-staining is the only evidence, so the location is gene-level and orthology-based for the rat product.
Proposed replacements: junctional membrane complex
Supporting Evidence:
PMID:23818870
The expression of MTMR12 was restricted to triads as no co-localization was observed with Ξ±-actinin at Z-lines
PMID:23818870
colocalize at the resolution of confocal microscopy (Figure 1D)

Core Functions

Catalytically inactive myotubularin-family partner that binds the active lipid phosphatase MTM1 (myotubularin), keeps it in the cytoplasm and maintains its protein abundance, supporting triad and myofibre maintenance in skeletal muscle. Evidence is from human cells, mouse muscle and cells, and zebrafish, transferred within PANTHER subfamily PTHR10807:SF37. The rat product keeps the whole pseudophosphatase domain and C-terminal region of the canonical protein, so the transfer covers it, but its own MTM1 binding has not been tested.

Molecular Function:
phosphatase binding
Directly Involved In:
protein stabilization
Cellular Locations:
cytoplasm sarcoplasmic reticulum
Supporting Evidence:
  • PMID:23818870
    binds to myotubularin in skeletal muscle
  • PMID:23818870
    MTMR12 primarily regulates the function of myotubularin protein by affecting protein levels instead of modulating the enzymatic activity
  • PMID:12847286
    coexpression of 3-PAP with myotubularin led to attenuation of the plasma membrane phenotype, associated with myotubularin relocalization to the cytosol
  • file:rat/Mtmr12/Mtmr12-bioinformatics/RESULTS-rereview.md
    the catalytic cysteine and arginine are absent in every MTMR12 product

References

Loading supporting content…

Download this section (compressed HTML)

Suggested Questions for Experts

Q: Is the alternative first exon that gives A0A8I5ZMD5 its 40-residue N-terminus transcribed and translated in rat tissue, or is it an Ensembl gene-model artifact relative to the cDNA-supported Q5FVM6 product?

Q: Should MTMR12's noncatalytic stabilization of MTM1 be captured by a regulator MF term (for example a phosphatase-stabilizing activity), given that the evidence argues against an effect on MTM1 catalytic activity and so against GO:0019211 phosphatase activator activity?

Suggested Experiments

Experiment: RT-PCR or long-read RNA-seq of rat skeletal muscle across the Mtmr12 5' region to test whether the alternative first exon is used, followed by co-immunoprecipitation of the encoded product with MTM1.

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML Β· Mtmr12-protnlm-predictions-review.yaml Β· Review status: COMPLETE

MTMR12 is a catalytically inactive myotubularin-family protein that binds and stabilizes MTM1 in the cytoplasm and localizes with it at skeletal-muscle triads. The selected product is an alternative gene model that differs from the canonical rat product only in its first 40 residues and keeps the whole pseudophosphatase domain. The single ProtNLM2 prediction, cytoplasm, is correct but less precise than the sarcoplasmic reticulum annotation the gene already carries.

Source documents: genes/rat/Mtmr12/Mtmr12-protnlm-source.json Β· genes/rat/Mtmr12/Mtmr12-notes.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0005737 cytoplasm GO_CC
LSP β€” Less precise than existing annotation Review score: 2/2
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-09-10 Β· file:rat/Mtmr12/Mtmr12-protnlm-source.json
Review rationale: MTMR12 is cytoplasmic, as shown for tagged human 3-PAP in COS-7 cells, where it also draws MTM1 into the cytoplasm, and in muscle it sits with MTM1 at triads overlapping the sarcoplasmic reticulum marker RyR1. The rat gene already carries GO:0016529 sarcoplasmic reticulum, accepted in the gene review, and cytoplasm is an ancestor of that term (OLS4), so the prediction is correct but less precise than an existing supported annotation. The selected product differs from the canonical rat product only in its first 40 residues, so the gene-level localization applies to it; the computational signal peptide on that alternative N-terminus does not establish secretion.
Supporting Evidence:

Deep Research

Falcon

(Mtmr12-deep-research-falcon.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“š Additional Documentation

Notes

(Mtmr12-notes.md)

Loading supporting content…

Download this section (compressed HTML)

Bioinformatics Results

(RESULTS.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“„ View Raw YAML

Loading supporting content…

Download this section (compressed HTML)