UniProt functional annotation for O75340



	UniProt functional annotation for O75340

UniProt code: O75340.

Organism: Homo sapiens (Human).

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

Function: Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes (PubMed:20691033, PubMed:25667979). Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes (PubMed:19520058). Together with PEF1, acts as calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats (PubMed:27716508). In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification (PubMed:27716508). Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway (PubMed:19864416). Promotes localization and polymerization of TFG at endoplasmic reticulum exit site (PubMed:27813252). Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis (By similarity). May mediate Ca(2+)-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity (PubMed:16132846). Its role in apoptosis may however be indirect, as suggested by knockout experiments (By similarity). May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway (PubMed:21893193). In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution (PubMed:27784779). {ECO:0000250|UniProtKB:P12815, ECO:0000269|PubMed:16132846, ECO:0000269|PubMed:19520058, ECO:0000269|PubMed:19864416, ECO:0000269|PubMed:20691033, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:25667979, ECO:0000269|PubMed:27716508, ECO:0000269|PubMed:27784779, ECO:0000269|PubMed:27813252}.

Function: [Isoform 2]: Has a lower Ca(2+) affinity than isoform 1 (By similarity). {ECO:0000250|UniProtKB:P12815}.

Subunit: Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1 (PubMed:11278427, PubMed:11883899, PubMed:27784779). Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain) (By similarity). Interacts with PDCD6IP; the interaction is calcium-dependent (PubMed:16957052, PubMed:18256029, PubMed:18940611, PubMed:20691033, PubMed:25667979). Interacts with RBM22 (PubMed:17045351). Interacts with PLSCR4 (PubMed:18256029). Interacts with ANXA7 and TSG101 (PubMed:18256029, PubMed:20691033). Interacts with DAPK1 (PubMed:16132846). Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A (PubMed:16957052, PubMed:18256029, PubMed:27716508, PubMed:25667979). Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent (PubMed:11883939, PubMed:18256029, PubMed:18940611). Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent (PubMed:18256029). Interacts with MCOLN1; the interaction is calcium-dependent (PubMed:19864416). Interacts with KDR; the interaction is calcium-dependent (PubMed:21893193). Interacts with HEBP2; the interaction is calcium- dependent (PubMed:27784779). Interacts with TFG (PubMed:27813252). Isoform 1: Interacts with SHISA5, leading to stabilize it (PubMed:17889823). Isoform 2: Does not interact with SHISA5 (PubMed:17889823). Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11 (PubMed:18256029, PubMed:20691033). {ECO:0000250|UniProtKB:P12815, ECO:0000269|PubMed:11278427, ECO:0000269|PubMed:11883899, ECO:0000269|PubMed:11883939, ECO:0000269|PubMed:16132846, ECO:0000269|PubMed:16957052, ECO:0000269|PubMed:17045351, ECO:0000269|PubMed:17889823, ECO:0000269|PubMed:18256029, ECO:0000269|PubMed:18940611, ECO:0000269|PubMed:19864416, ECO:0000269|PubMed:20691033, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:25667979, ECO:0000269|PubMed:27716508, ECO:0000269|PubMed:27784779, ECO:0000269|PubMed:27813252}.

Subcellular location: Endoplasmic reticulum membrane {ECO:0000269|PubMed:16957052, ECO:0000269|PubMed:27813252}; Peripheral membrane protein {ECO:0000269|PubMed:16957052}. Cytoplasmic vesicle, COPII-coated vesicle membrane {ECO:0000269|PubMed:27716508}. Cytoplasm {ECO:0000269|PubMed:27716508, ECO:0000269|PubMed:27784779}. Nucleus {ECO:0000269|PubMed:17045351, ECO:0000269|PubMed:21122810, ECO:0000269|PubMed:27784779}. Endosome {ECO:0000269|PubMed:19864416}. Note=Interaction with RBM22 induces relocalization from the cytoplasm to the nucleus (PubMed:17045351). Translocated from the cytoplasm to the nucleus after heat shock cell treatment. Accumulates in cytoplasmic vesicle-like organelles after heat shock treatment, which may represent stress granules (PubMed:21122810). In response to calcium increase, relocates from cytoplasm to COPII vesicle coat (PubMed:27716508). Localizes to endoplasmic reticulum exit site (ERES) (PubMed:27813252). {ECO:0000269|PubMed:17045351, ECO:0000269|PubMed:21122810, ECO:0000269|PubMed:27716508, ECO:0000269|PubMed:27813252}.

Domain: Interacts with different set of proteins thanks to 3 different hydrophobic pockets (PubMed:20691033, PubMed:25667979). Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr- 180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2) (PubMed:20691033). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF- hand 1 (EF1) to 3 (EF3) (PubMed:25667979). {ECO:0000269|PubMed:20691033, ECO:0000269|PubMed:25667979}.

Domain: EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium- binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity (PubMed:18940611, PubMed:20691033). A one-residue insertion in the EF5- binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand (PubMed:18940611, PubMed:20691033). EF5 acts as a high-affinity magnesium-binding domain instead (By similarity). Magnesium, may affect dimerization (By similarity). EF5 may bind either calcium or magnesium depending on the context (By similarity). {ECO:0000250|UniProtKB:P12815, ECO:0000269|PubMed:18940611, ECO:0000269|PubMed:20691033}.

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:		Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes (PubMed:20691033, PubMed:25667979). Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes (PubMed:19520058). Together with PEF1, acts as calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats (PubMed:27716508). In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification (PubMed:27716508). Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway (PubMed:19864416). Promotes localization and polymerization of TFG at endoplasmic reticulum exit site (PubMed:27813252). Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis (By similarity). May mediate Ca(2+)-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity (PubMed:16132846). Its role in apoptosis may however be indirect, as suggested by knockout experiments (By similarity). May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway (PubMed:21893193). In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution (PubMed:27784779). {ECO:0000250\|UniProtKB:P12815, ECO:0000269\|PubMed:16132846, ECO:0000269\|PubMed:19520058, ECO:0000269\|PubMed:19864416, ECO:0000269\|PubMed:20691033, ECO:0000269\|PubMed:21893193, ECO:0000269\|PubMed:25667979, ECO:0000269\|PubMed:27716508, ECO:0000269\|PubMed:27784779, ECO:0000269\|PubMed:27813252}.



Function:		[Isoform 2]: Has a lower Ca(2+) affinity than isoform 1 (By similarity). {ECO:0000250\|UniProtKB:P12815}.


Subunit:		Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1 (PubMed:11278427, PubMed:11883899, PubMed:27784779). Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain) (By similarity). Interacts with PDCD6IP; the interaction is calcium-dependent (PubMed:16957052, PubMed:18256029, PubMed:18940611, PubMed:20691033, PubMed:25667979). Interacts with RBM22 (PubMed:17045351). Interacts with PLSCR4 (PubMed:18256029). Interacts with ANXA7 and TSG101 (PubMed:18256029, PubMed:20691033). Interacts with DAPK1 (PubMed:16132846). Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A (PubMed:16957052, PubMed:18256029, PubMed:27716508, PubMed:25667979). Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent (PubMed:11883939, PubMed:18256029, PubMed:18940611). Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent (PubMed:18256029). Interacts with MCOLN1; the interaction is calcium-dependent (PubMed:19864416). Interacts with KDR; the interaction is calcium-dependent (PubMed:21893193). Interacts with HEBP2; the interaction is calcium- dependent (PubMed:27784779). Interacts with TFG (PubMed:27813252). Isoform 1: Interacts with SHISA5, leading to stabilize it (PubMed:17889823). Isoform 2: Does not interact with SHISA5 (PubMed:17889823). Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11 (PubMed:18256029, PubMed:20691033). {ECO:0000250\|UniProtKB:P12815, ECO:0000269\|PubMed:11278427, ECO:0000269\|PubMed:11883899, ECO:0000269\|PubMed:11883939, ECO:0000269\|PubMed:16132846, ECO:0000269\|PubMed:16957052, ECO:0000269\|PubMed:17045351, ECO:0000269\|PubMed:17889823, ECO:0000269\|PubMed:18256029, ECO:0000269\|PubMed:18940611, ECO:0000269\|PubMed:19864416, ECO:0000269\|PubMed:20691033, ECO:0000269\|PubMed:21893193, ECO:0000269\|PubMed:25667979, ECO:0000269\|PubMed:27716508, ECO:0000269\|PubMed:27784779, ECO:0000269\|PubMed:27813252}.
Subcellular location:		Endoplasmic reticulum membrane {ECO:0000269\|PubMed:16957052, ECO:0000269\|PubMed:27813252}; Peripheral membrane protein {ECO:0000269\|PubMed:16957052}. Cytoplasmic vesicle, COPII-coated vesicle membrane {ECO:0000269\|PubMed:27716508}. Cytoplasm {ECO:0000269\|PubMed:27716508, ECO:0000269\|PubMed:27784779}. Nucleus {ECO:0000269\|PubMed:17045351, ECO:0000269\|PubMed:21122810, ECO:0000269\|PubMed:27784779}. Endosome {ECO:0000269\|PubMed:19864416}. Note=Interaction with RBM22 induces relocalization from the cytoplasm to the nucleus (PubMed:17045351). Translocated from the cytoplasm to the nucleus after heat shock cell treatment. Accumulates in cytoplasmic vesicle-like organelles after heat shock treatment, which may represent stress granules (PubMed:21122810). In response to calcium increase, relocates from cytoplasm to COPII vesicle coat (PubMed:27716508). Localizes to endoplasmic reticulum exit site (ERES) (PubMed:27813252). {ECO:0000269\|PubMed:17045351, ECO:0000269\|PubMed:21122810, ECO:0000269\|PubMed:27716508, ECO:0000269\|PubMed:27813252}.
Domain:		Interacts with different set of proteins thanks to 3 different hydrophobic pockets (PubMed:20691033, PubMed:25667979). Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr- 180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2) (PubMed:20691033). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF- hand 1 (EF1) to 3 (EF3) (PubMed:25667979). {ECO:0000269\|PubMed:20691033, ECO:0000269\|PubMed:25667979}.
Domain:		EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium- binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity (PubMed:18940611, PubMed:20691033). A one-residue insertion in the EF5- binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand (PubMed:18940611, PubMed:20691033). EF5 acts as a high-affinity magnesium-binding domain instead (By similarity). Magnesium, may affect dimerization (By similarity). EF5 may bind either calcium or magnesium depending on the context (By similarity). {ECO:0000250\|UniProtKB:P12815, ECO:0000269\|PubMed:18940611, ECO:0000269\|PubMed:20691033}.