{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q4VAE3","secondaryAccessions":["Q810S8"],"uniProtkbId":"TMM65_MOUSE","entryAudit":{"firstPublicDate":"2006-10-03","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2005-07-05","entryVersion":115,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Mus musculus","commonName":"Mouse","taxonId":10090,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Glires","Rodentia","Myomorpha","Muroidea","Muridae","Murinae","Mus","Mus"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Transmembrane protein 65"}},"flag":"Precursor"},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"26403541"},{"evidenceCode":"ECO:0000312","source":"MGI","id":"MGI:1922118"}],"value":"Tmem65"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6PI78"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26403541"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36257954"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40200126"}],"value":"Mitochondrial protein that plays a critical role in the sodium-dependent calcium efflux from mitochondrion (PubMed:40200126). The precise role of TMEM65 in mitochondrial sodium/calcium exchange is however unclear: TMEM65 associates with the SLC8B1/NCLX antiporter and probably promotes the sodium/calcium exchange mediated by SLC8B1/NCLX (By similarity). According to another report, TMEM65 functions as the mitochondrial sodium/calcium antiporter itself: homodimerization drives formation of a pocket capable of binding calcium (By similarity). Essential for maintaining proper cardiac intercalated disk (ICD) structure and function as well as cardiac conduction velocity in the heart (PubMed:36257954). Its association with SCN1B is required for stabilizing the perinexus in the ICD and for localization of GJA1 and SCN5A to the ICD (PubMed:26403541, PubMed:36257954)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6PI78"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26403541"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36257954"}],"value":"Monomer (PubMed:26403541). Homodimer (PubMed:26403541). Interacts with SLC8B1/NCLX; required for SLC8B1/NCLX antiporter activity (By similarity). Interacts with GJA1 (PubMed:26403541). Interacts weakly with DSP (PubMed:26403541). Interacts with SCN1B (PubMed:36257954)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26403541"}],"value":"Localizes at the intercalated disk in ventricular tissue and cardiomyocytes"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6PI78"}],"value":"Mitochondrion inner membrane","id":"SL-0168"},"topology":{"evidences":[{"evidenceCode":"ECO:0000255"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26403541"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000255"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26403541"}],"value":"Predominantly expressed in the ventricular tissue (at protein level)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26403541"}],"value":"Low level expression seen in the heart between 8.5 dpc and 15.5 dpc. Expression levels increase progressively after birth, with the highest levels seen in adults"}],"commentType":"DEVELOPMENTAL STAGE"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36257954"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40200126"}],"value":"Knockdown leads to irregular staining patterns of perinexal proteins, altered calcium and potassium currents, impaired cardiac conduction, and intercalated disks structural defects in both cellular and histological levels (PubMed:36257954). Hearts ultimately develop dilated cardiomyopathy, severe fibrosis and congestive heart failure (PubMed:36257954). Mitochondrial calcium overload in the heart and skeletal muscle, impairing both cardiac and neuromuscular function(PubMed:40200126)"}],"commentType":"DISRUPTION PHENOTYPE"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the TMEM65 family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAH49380.1","note":"Truncated N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Transit peptide","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":55,"modifier":"EXACT"}},"description":"Mitochondrion","evidences":[{"evidenceCode":"ECO:0000255"}]},{"type":"Chain","location":{"start":{"value":56,"modifier":"EXACT"},"end":{"value":234,"modifier":"EXACT"}},"description":"Transmembrane protein 65","featureId":"PRO_0000251405"},{"type":"Topological 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