UniProt functional annotation for O75923



	UniProt functional annotation for O75923

UniProt code: O75923.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress (By similarity). {ECO:0000250}.

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000255|PROSITE-ProRule:PRU00041};

Subunit: Interacts with CACNA1S. Interacts with ANXA1; the interaction is Ca(2+)- and injury state-dependent. Interacts with ANXA2; the interaction is Ca(2+)- and injury state-dependent. Interacts with CACNA1S and PARVB. Interacts with TRIM72/MG53; interaction is required for transport to sites of cell injury during repair patch formation (By similarity). Interacts with RIPOR2; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with CAV3 and PARVB. Interacts with AHNAK; the interaction is direct and Ca(2+)- independent. Interacts with AHNAK2; the interaction is direct and Ca(2+)-independent. {ECO:0000250, ECO:0000269|PubMed:11532985, ECO:0000269|PubMed:15835269, ECO:0000269|PubMed:17185750, ECO:0000269|PubMed:24239457, ECO:0000269|PubMed:24687993}.

Subcellular location: Cell membrane, sarcolemma; Single-pass type II membrane protein. Cytoplasmic vesicle membrane {ECO:0000250}; Single- pass type II membrane protein {ECO:0000250}. Cell membrane. Note=Colocalizes, during muscle differentiation, with BIN1 in the T- tubule system of myotubules and at the site of contact between two myotubes or a myoblast and a myotube. Wounding of myotubes led to its focal enrichment to the site of injury and to its relocalization in a Ca(2+)-dependent manner toward the plasma membrane. Colocalizes with AHNAK, AHNAK2 and PARVB at the sarcolemma of skeletal muscle. Detected on the apical plasma membrane of the syncytiotrophoblast. Reaches the plasmma membrane through a caveolin-independent mechanism. Retained by caveolin at the plasmma membrane (By similarity). Colocalizes, during muscle differentiation, with CACNA1S in the T-tubule system of myotubules (By similarity). Accumulates and colocalizes with fusion vesicles at the sarcolemma disruption sites (By similarity). {ECO:0000250}.

Tissue specificity: Expressed in skeletal muscle, myoblast, myotube and in the syncytiotrophoblast (STB) of the placenta (at protein level). Ubiquitous. Highly expressed in skeletal muscle. Also found in heart, brain, spleen, intestine, placenta and at lower levels in liver, lung, kidney and pancreas. {ECO:0000269|PubMed:10196375, ECO:0000269|PubMed:11532985, ECO:0000269|PubMed:11959863, ECO:0000269|PubMed:15318348, ECO:0000269|PubMed:16896923, ECO:0000269|PubMed:17185750, ECO:0000269|PubMed:17363620, ECO:0000269|PubMed:17554076, ECO:0000269|PubMed:24239457}.

Developmental stage: Expression in limb tissue from 5-6 weeks embryos; persists throughout development. {ECO:0000269|PubMed:10196375}.

Domain: All seven C2 domains associate with lipid membranes in a calcium-dependent manner. Domains C2 1 and 3 have the highest affinity for calcium, the C2 domain 1 seems to be largely unstructured in the absence of bound ligands. The C2 domain 1 from isoform 14 does not bind calcium in the absence of bound phospholipid (PubMed:24239457, PubMed:24461013). {ECO:0000269|PubMed:24239457, ECO:0000269|PubMed:24461013}.

Disease: Muscular dystrophy, limb-girdle, autosomal recessive 2 (LGMDR2) [MIM:253601]: An autosomal recessive degenerative myopathy characterized by weakness and atrophy starting in the proximal pelvifemoral muscles, with onset in the late teens or later, massive elevation of serum creatine kinase levels and slow progression. Scapular muscle involvement is minor and not present at onset. Upper limb girdle involvement follows some years after the onset in lower limbs. {ECO:0000269|PubMed:10196377, ECO:0000269|PubMed:11134403, ECO:0000269|PubMed:14678801, ECO:0000269|PubMed:15469449, ECO:0000269|PubMed:16010686, ECO:0000269|PubMed:16100712, ECO:0000269|PubMed:16705711, ECO:0000269|PubMed:16996541, ECO:0000269|PubMed:17185750, ECO:0000269|PubMed:17287450, ECO:0000269|PubMed:18306167, ECO:0000269|PubMed:18853459, ECO:0000269|PubMed:19084402, ECO:0000269|PubMed:9731526}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Miyoshi muscular dystrophy 1 (MMD1) [MIM:254130]: A late-onset muscular dystrophy involving the distal lower limb musculature. It is characterized by weakness that initially affects the gastrocnemius muscle during early adulthood. {ECO:0000269|PubMed:10196377, ECO:0000269|PubMed:11134403, ECO:0000269|PubMed:11468312, ECO:0000269|PubMed:11959863, ECO:0000269|PubMed:12796534, ECO:0000269|PubMed:15116377, ECO:0000269|PubMed:15469449, ECO:0000269|PubMed:15477515, ECO:0000269|PubMed:15515206, ECO:0000269|PubMed:16010686, ECO:0000269|PubMed:16100712, ECO:0000269|PubMed:17287450, ECO:0000269|PubMed:18306167, ECO:0000269|PubMed:18853459, ECO:0000269|PubMed:9731526, ECO:0000269|Ref.28}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Distal myopathy with anterior tibial onset (DMAT) [MIM:606768]: Onset of the disorder is between 14 and 28 years of age and the anterior tibial muscles are the first muscle group to be involved. Inheritance is autosomal recessive. {ECO:0000269|PubMed:11198284}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 14]: Produced by alternative promoter usage. {ECO:0000305}.

Similarity: Belongs to the ferlin family. {ECO:0000305}.

Sequence caution: Sequence=BAG51981.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=CAA07603.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAA07603.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress (By similarity). {ECO:0000250}.


Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00041};
Subunit:		Interacts with CACNA1S. Interacts with ANXA1; the interaction is Ca(2+)- and injury state-dependent. Interacts with ANXA2; the interaction is Ca(2+)- and injury state-dependent. Interacts with CACNA1S and PARVB. Interacts with TRIM72/MG53; interaction is required for transport to sites of cell injury during repair patch formation (By similarity). Interacts with RIPOR2; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with CAV3 and PARVB. Interacts with AHNAK; the interaction is direct and Ca(2+)- independent. Interacts with AHNAK2; the interaction is direct and Ca(2+)-independent. {ECO:0000250, ECO:0000269\|PubMed:11532985, ECO:0000269\|PubMed:15835269, ECO:0000269\|PubMed:17185750, ECO:0000269\|PubMed:24239457, ECO:0000269\|PubMed:24687993}.
Subcellular location:		Cell membrane, sarcolemma; Single-pass type II membrane protein. Cytoplasmic vesicle membrane {ECO:0000250}; Single- pass type II membrane protein {ECO:0000250}. Cell membrane. Note=Colocalizes, during muscle differentiation, with BIN1 in the T- tubule system of myotubules and at the site of contact between two myotubes or a myoblast and a myotube. Wounding of myotubes led to its focal enrichment to the site of injury and to its relocalization in a Ca(2+)-dependent manner toward the plasma membrane. Colocalizes with AHNAK, AHNAK2 and PARVB at the sarcolemma of skeletal muscle. Detected on the apical plasma membrane of the syncytiotrophoblast. Reaches the plasmma membrane through a caveolin-independent mechanism. Retained by caveolin at the plasmma membrane (By similarity). Colocalizes, during muscle differentiation, with CACNA1S in the T-tubule system of myotubules (By similarity). Accumulates and colocalizes with fusion vesicles at the sarcolemma disruption sites (By similarity). {ECO:0000250}.
Tissue specificity:		Expressed in skeletal muscle, myoblast, myotube and in the syncytiotrophoblast (STB) of the placenta (at protein level). Ubiquitous. Highly expressed in skeletal muscle. Also found in heart, brain, spleen, intestine, placenta and at lower levels in liver, lung, kidney and pancreas. {ECO:0000269\|PubMed:10196375, ECO:0000269\|PubMed:11532985, ECO:0000269\|PubMed:11959863, ECO:0000269\|PubMed:15318348, ECO:0000269\|PubMed:16896923, ECO:0000269\|PubMed:17185750, ECO:0000269\|PubMed:17363620, ECO:0000269\|PubMed:17554076, ECO:0000269\|PubMed:24239457}.
Developmental stage:		Expression in limb tissue from 5-6 weeks embryos; persists throughout development. {ECO:0000269\|PubMed:10196375}.
Domain:		All seven C2 domains associate with lipid membranes in a calcium-dependent manner. Domains C2 1 and 3 have the highest affinity for calcium, the C2 domain 1 seems to be largely unstructured in the absence of bound ligands. The C2 domain 1 from isoform 14 does not bind calcium in the absence of bound phospholipid (PubMed:24239457, PubMed:24461013). {ECO:0000269\|PubMed:24239457, ECO:0000269\|PubMed:24461013}.
Disease:		Muscular dystrophy, limb-girdle, autosomal recessive 2 (LGMDR2) [MIM:253601]: An autosomal recessive degenerative myopathy characterized by weakness and atrophy starting in the proximal pelvifemoral muscles, with onset in the late teens or later, massive elevation of serum creatine kinase levels and slow progression. Scapular muscle involvement is minor and not present at onset. Upper limb girdle involvement follows some years after the onset in lower limbs. {ECO:0000269\|PubMed:10196377, ECO:0000269\|PubMed:11134403, ECO:0000269\|PubMed:14678801, ECO:0000269\|PubMed:15469449, ECO:0000269\|PubMed:16010686, ECO:0000269\|PubMed:16100712, ECO:0000269\|PubMed:16705711, ECO:0000269\|PubMed:16996541, ECO:0000269\|PubMed:17185750, ECO:0000269\|PubMed:17287450, ECO:0000269\|PubMed:18306167, ECO:0000269\|PubMed:18853459, ECO:0000269\|PubMed:19084402, ECO:0000269\|PubMed:9731526}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Miyoshi muscular dystrophy 1 (MMD1) [MIM:254130]: A late-onset muscular dystrophy involving the distal lower limb musculature. It is characterized by weakness that initially affects the gastrocnemius muscle during early adulthood. {ECO:0000269\|PubMed:10196377, ECO:0000269\|PubMed:11134403, ECO:0000269\|PubMed:11468312, ECO:0000269\|PubMed:11959863, ECO:0000269\|PubMed:12796534, ECO:0000269\|PubMed:15116377, ECO:0000269\|PubMed:15469449, ECO:0000269\|PubMed:15477515, ECO:0000269\|PubMed:15515206, ECO:0000269\|PubMed:16010686, ECO:0000269\|PubMed:16100712, ECO:0000269\|PubMed:17287450, ECO:0000269\|PubMed:18306167, ECO:0000269\|PubMed:18853459, ECO:0000269\|PubMed:9731526, ECO:0000269\|Ref.28}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Distal myopathy with anterior tibial onset (DMAT) [MIM:606768]: Onset of the disorder is between 14 and 28 years of age and the anterior tibial muscles are the first muscle group to be involved. Inheritance is autosomal recessive. {ECO:0000269\|PubMed:11198284}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 14]: Produced by alternative promoter usage. {ECO:0000305}.
Similarity:		Belongs to the ferlin family. {ECO:0000305}.
Sequence caution:		Sequence=BAG51981.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=CAA07603.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAA07603.1; Type=Frameshift; Evidence={ECO:0000305};