UniProt functional annotation for P14735



	UniProt functional annotation for P14735

UniProt code: P14735.

Organism: Homo sapiens (Human).

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

Function: Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling (PubMed:2293021, PubMed:10684867, PubMed:26968463, PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446, PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:29596046, PubMed:21098034). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046). Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP (By similarity). Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (PubMed:9830016, PubMed:26394692) (Probable). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (PubMed:21098034). Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I. {ECO:0000250|UniProtKB:Q9JHR7, ECO:0000269|PubMed:10684867, ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:17613531, ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:20364150, ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:2293021, ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:24847884, ECO:0000269|PubMed:26394692, ECO:0000269|PubMed:26968463, ECO:0000269|PubMed:29596046, ECO:0000269|PubMed:9830016, ECO:0000305|PubMed:23922390}.

Function: (Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV). {ECO:0000269|PubMed:17055432, ECO:0000269|PubMed:17553876}.

Catalytic activity: Reaction=Degradation of insulin, glucagon and other polypeptides. No action on proteins.; EC=3.4.24.56; Evidence={ECO:0000269|PubMed:10684867, ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:17613531, ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:2293021, ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:24847884, ECO:0000269|PubMed:26394692, ECO:0000269|PubMed:29596046};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:26394692}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:18986166, ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:21098034, ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:26394692};

Activity regulation: Activated by small peptides (By similarity). Activated by ATP and GTP, and to a lesser extent by CTP, TTP and PPPi (PubMed:17613531). Inhibited by bacitracin (PubMed:17055432, PubMed:17613531). In vitro modification of Cys residues impairs enzyme activity (PubMed:18986166). {ECO:0000250, ECO:0000269|PubMed:17055432, ECO:0000269|PubMed:17613531, ECO:0000269|PubMed:18986166}.

Subunit: Homodimer (PubMed:17051221, PubMed:19321446, PubMed:23922390, PubMed:26394692, PubMed:29596046) (Probable). Can also form homotetramers (By similarity). {ECO:0000250|UniProtKB:P35559, ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:19321446, ECO:0000269|PubMed:23922390, ECO:0000269|PubMed:26394692, ECO:0000269|PubMed:29596046, ECO:0000305|PubMed:17613531}.

Subunit: (Microbial infection) Interacts (via N-terminus) with varicella-zoster virus (VZV) envelope glycoprotein E (via N-terminus); the membrane-associated isoform may function as an entry receptor for this virus (PubMed:17055432, PubMed:17553876). {ECO:0000269|PubMed:17055432, ECO:0000269|PubMed:17553876}.

Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:20364150, ECO:0000269|PubMed:9830016}. Cell membrane {ECO:0000250|UniProtKB:P35559}. Secreted {ECO:0000269|PubMed:9830016}. Note=Present at the cell surface of neuron cells. The membrane- associated isoform is approximately 5 kDa larger than the known cytosolic isoform.

Tissue specificity: Detected in brain and in cerebrospinal fluid (at protein level). {ECO:0000269|PubMed:9830016}.

Domain: The SlyX motif may be involved in the non-conventional secretion of the protein. {ECO:0000250|UniProtKB:Q9JHR7}.

Ptm: The N-terminus is blocked.

Miscellaneous: ATP-binding induces a conformation change. {ECO:0000269|PubMed:17613531}.

Similarity: Belongs to the peptidase M16 family. {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:		Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling (PubMed:2293021, PubMed:10684867, PubMed:26968463, PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446, PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:29596046, PubMed:21098034). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046). Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP (By similarity). Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (PubMed:9830016, PubMed:26394692) (Probable). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (PubMed:21098034). Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I. {ECO:0000250\|UniProtKB:Q9JHR7, ECO:0000269\|PubMed:10684867, ECO:0000269\|PubMed:17051221, ECO:0000269\|PubMed:17613531, ECO:0000269\|PubMed:18986166, ECO:0000269\|PubMed:19321446, ECO:0000269\|PubMed:20364150, ECO:0000269\|PubMed:21098034, ECO:0000269\|PubMed:2293021, ECO:0000269\|PubMed:23922390, ECO:0000269\|PubMed:24847884, ECO:0000269\|PubMed:26394692, ECO:0000269\|PubMed:26968463, ECO:0000269\|PubMed:29596046, ECO:0000269\|PubMed:9830016, ECO:0000305\|PubMed:23922390}.



Function:		(Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV). {ECO:0000269\|PubMed:17055432, ECO:0000269\|PubMed:17553876}.


Catalytic activity:		Reaction=Degradation of insulin, glucagon and other polypeptides. No action on proteins.; EC=3.4.24.56; Evidence={ECO:0000269\|PubMed:10684867, ECO:0000269\|PubMed:17051221, ECO:0000269\|PubMed:17613531, ECO:0000269\|PubMed:18986166, ECO:0000269\|PubMed:19321446, ECO:0000269\|PubMed:21098034, ECO:0000269\|PubMed:2293021, ECO:0000269\|PubMed:23922390, ECO:0000269\|PubMed:24847884, ECO:0000269\|PubMed:26394692, ECO:0000269\|PubMed:29596046};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:17051221, ECO:0000269\|PubMed:18986166, ECO:0000269\|PubMed:19321446, ECO:0000269\|PubMed:21098034, ECO:0000269\|PubMed:23922390, ECO:0000269\|PubMed:26394692}; Note=Binds 1 zinc ion per subunit. {ECO:0000269\|PubMed:17051221, ECO:0000269\|PubMed:18986166, ECO:0000269\|PubMed:19321446, ECO:0000269\|PubMed:21098034, ECO:0000269\|PubMed:23922390, ECO:0000269\|PubMed:26394692};
Activity regulation:		Activated by small peptides (By similarity). Activated by ATP and GTP, and to a lesser extent by CTP, TTP and PPPi (PubMed:17613531). Inhibited by bacitracin (PubMed:17055432, PubMed:17613531). In vitro modification of Cys residues impairs enzyme activity (PubMed:18986166). {ECO:0000250, ECO:0000269\|PubMed:17055432, ECO:0000269\|PubMed:17613531, ECO:0000269\|PubMed:18986166}.
Subunit:		Homodimer (PubMed:17051221, PubMed:19321446, PubMed:23922390, PubMed:26394692, PubMed:29596046) (Probable). Can also form homotetramers (By similarity). {ECO:0000250\|UniProtKB:P35559, ECO:0000269\|PubMed:17051221, ECO:0000269\|PubMed:19321446, ECO:0000269\|PubMed:23922390, ECO:0000269\|PubMed:26394692, ECO:0000269\|PubMed:29596046, ECO:0000305\|PubMed:17613531}.
Subunit:		(Microbial infection) Interacts (via N-terminus) with varicella-zoster virus (VZV) envelope glycoprotein E (via N-terminus); the membrane-associated isoform may function as an entry receptor for this virus (PubMed:17055432, PubMed:17553876). {ECO:0000269\|PubMed:17055432, ECO:0000269\|PubMed:17553876}.
Subcellular location:		Cytoplasm, cytosol {ECO:0000269\|PubMed:20364150, ECO:0000269\|PubMed:9830016}. Cell membrane {ECO:0000250\|UniProtKB:P35559}. Secreted {ECO:0000269\|PubMed:9830016}. Note=Present at the cell surface of neuron cells. The membrane- associated isoform is approximately 5 kDa larger than the known cytosolic isoform.
Tissue specificity:		Detected in brain and in cerebrospinal fluid (at protein level). {ECO:0000269\|PubMed:9830016}.
Domain:		The SlyX motif may be involved in the non-conventional secretion of the protein. {ECO:0000250\|UniProtKB:Q9JHR7}.
Ptm:		The N-terminus is blocked.
Miscellaneous:		ATP-binding induces a conformation change. {ECO:0000269\|PubMed:17613531}.
Similarity:		Belongs to the peptidase M16 family. {ECO:0000305}.