UniProt functional annotation for P56817



	UniProt functional annotation for P56817

UniProt code: P56817.

Organism: Homo sapiens (Human).

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

Function: Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:10656250, ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:20354142}.

Catalytic activity: Reaction=Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-|- Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein.; EC=3.4.23.46; Evidence={ECO:0000269|PubMed:10677483};

Activity regulation: Inhibited by RTN3 and RTN4. {ECO:0000269|PubMed:15286784, ECO:0000269|PubMed:16965550}.

Biophysicochemical properties: Kinetic parameters: KM=15.2 mM for APP cleaved by PSEN1 (at pH4) {ECO:0000269|PubMed:10677483}; KM=1 mM for APP Swedish variant (at pH4) {ECO:0000269|PubMed:10677483}; Note=kcat is 0.67 sec(-1) and 2.45 sec(-1) for APP cleaved by PSEN1 and APP Swedish variant, respectively (PubMed:10677483). {ECO:0000269|PubMed:10677483};

Subunit: Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN1; RTN2; RTN3 and RTN4; the interaction leads to inhibition of amyloid precursor protein processing (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed:20354142). Interacts with PCSK9 (PubMed:18660751). Interacts with NAT8 and NAT8B (PubMed:19011241). Interacts with BIN1 (PubMed:27179792). Interacts (via extracellular domain) with ADAM10 (via extracellular domain) (By similarity). Interacts with SORL1; this interaction may affect binding with APP and hence reduce APP cleavage (PubMed:16407538). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:14567678, ECO:0000269|PubMed:15286784, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:16407538, ECO:0000269|PubMed:16965550, ECO:0000269|PubMed:16979658, ECO:0000269|PubMed:18660751, ECO:0000269|PubMed:19011241, ECO:0000269|PubMed:20354142, ECO:0000269|PubMed:27179792}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:11466313}; Single-pass type I membrane protein {ECO:0000305|PubMed:11466313}. Golgi apparatus, trans-Golgi network {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15615712, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:20354142, ECO:0000269|PubMed:23109336}. Endoplasmic reticulum {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:17425515}. Endosome {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016}. Cell surface {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:23109336}. Cytoplasmic vesicle membrane {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016}; Single-pass type I membrane protein {ECO:0000305|PubMed:11466313}. Membrane raft {ECO:0000250|UniProtKB:P56818}. Lysosome {ECO:0000269|PubMed:16033761, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Late endosome {ECO:0000269|PubMed:16033761, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Early endosome {ECO:0000269|PubMed:15615712, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Recycling endosome {ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Cell projection, axon {ECO:0000250|UniProtKB:P56818}. Cell projection, dendrite {ECO:0000250|UniProtKB:P56818}. Note=Predominantly localized to the later Golgi/trans-Golgi network (TGN) and minimally detectable in the early Golgi compartments. A small portion is also found in the endoplasmic reticulum, endosomes and on the cell surface (PubMed:17425515, PubMed:11466313). Colocalization with APP in early endosomes is due to addition of bisecting N-acetylglucosamine wich blocks targeting to late endosomes and lysosomes (By similarity). Retrogradly transported from endosomal compartments to the trans-Golgi network in a phosphorylation- and GGA1- dependent manner (PubMed:15886016). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:17425515}.

Tissue specificity: Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata. {ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:11083922}.

Induction: Up-regulated by the Ca(2+)-regulated transcription factor NFATC4. {ECO:0000269|PubMed:25663301}.

Domain: DXXLL motif is required for a proper endocytosis and retrograde transport to the trans-Golgi network, as well as for regulation of lysosomal degradation. {ECO:0000269|PubMed:23109336}.

Domain: The transmembrane domain is necessary for its activity. It determines its late Golgi localization and access to its substrate, APP. {ECO:0000269|PubMed:11466313}.

Ptm: N-Glycosylated (PubMed:11083922, PubMed:17425515). Addition of a bisecting N-acetylglucosamine by MGAT3 blocks lysosomal targeting, further degradation and is required for maintaining stability under stress conditions (By similarity). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:17425515}.

Ptm: Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys- 279, Lys-285, Lys-299, Lys-300 and Lys-307. Acetylation by NAT8 and NAT8B is transient and deacetylation probably occurs in the Golgi. Acetylation regulates the maturation, the transport to the plasma membrane, the stability and the expression of the protein. {ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241}.

Ptm: Palmitoylation mediates lipid raft localization. {ECO:0000250|UniProtKB:P56818}.

Ptm: Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation (PubMed:27302062, PubMed:16033761, PubMed:20484053, PubMed:23109336). Monoubiquitinated and 'Lys-63'-linked polyubitinated (PubMed:20484053). Deubiquitnated by USP8; inhibits lysosomal degradation (PubMed:27302062). {ECO:0000269|PubMed:16033761, ECO:0000269|PubMed:20484053, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27302062}.

Ptm: Phosphorylation at Ser-498 is required for interaction with GGA1 and retrograded transport from endosomal compartments to the trans- Golgi network. Non-phosphorylated BACE1 enters a direct recycling route to the cell surface. {ECO:0000269|PubMed:15886016}.

Similarity: Belongs to the peptidase A1 family. {ECO:0000305}.

Sequence caution: Sequence=BAA86463.2; 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:		Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). {ECO:0000250\|UniProtKB:P56818, ECO:0000269\|PubMed:10656250, ECO:0000269\|PubMed:10677483, ECO:0000269\|PubMed:20354142}.


Catalytic activity:		Reaction=Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-\|- Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein.; EC=3.4.23.46; Evidence={ECO:0000269\|PubMed:10677483};
Activity regulation:		Inhibited by RTN3 and RTN4. {ECO:0000269\|PubMed:15286784, ECO:0000269\|PubMed:16965550}.
Biophysicochemical properties:		Kinetic parameters: KM=15.2 mM for APP cleaved by PSEN1 (at pH4) {ECO:0000269\|PubMed:10677483}; KM=1 mM for APP Swedish variant (at pH4) {ECO:0000269\|PubMed:10677483}; Note=kcat is 0.67 sec(-1) and 2.45 sec(-1) for APP cleaved by PSEN1 and APP Swedish variant, respectively (PubMed:10677483). {ECO:0000269\|PubMed:10677483};
Subunit:		Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN1; RTN2; RTN3 and RTN4; the interaction leads to inhibition of amyloid precursor protein processing (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed:20354142). Interacts with PCSK9 (PubMed:18660751). Interacts with NAT8 and NAT8B (PubMed:19011241). Interacts with BIN1 (PubMed:27179792). Interacts (via extracellular domain) with ADAM10 (via extracellular domain) (By similarity). Interacts with SORL1; this interaction may affect binding with APP and hence reduce APP cleavage (PubMed:16407538). {ECO:0000250\|UniProtKB:P56818, ECO:0000269\|PubMed:14567678, ECO:0000269\|PubMed:15286784, ECO:0000269\|PubMed:15886016, ECO:0000269\|PubMed:16407538, ECO:0000269\|PubMed:16965550, ECO:0000269\|PubMed:16979658, ECO:0000269\|PubMed:18660751, ECO:0000269\|PubMed:19011241, ECO:0000269\|PubMed:20354142, ECO:0000269\|PubMed:27179792}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:11466313}; Single-pass type I membrane protein {ECO:0000305\|PubMed:11466313}. Golgi apparatus, trans-Golgi network {ECO:0000269\|PubMed:11466313, ECO:0000269\|PubMed:15615712, ECO:0000269\|PubMed:15886016, ECO:0000269\|PubMed:17425515, ECO:0000269\|PubMed:20354142, ECO:0000269\|PubMed:23109336}. Endoplasmic reticulum {ECO:0000269\|PubMed:11466313, ECO:0000269\|PubMed:17425515}. Endosome {ECO:0000269\|PubMed:11466313, ECO:0000269\|PubMed:15886016}. Cell surface {ECO:0000269\|PubMed:11466313, ECO:0000269\|PubMed:15886016, ECO:0000269\|PubMed:17425515, ECO:0000269\|PubMed:23109336}. Cytoplasmic vesicle membrane {ECO:0000269\|PubMed:11466313, ECO:0000269\|PubMed:15886016}; Single-pass type I membrane protein {ECO:0000305\|PubMed:11466313}. Membrane raft {ECO:0000250\|UniProtKB:P56818}. Lysosome {ECO:0000269\|PubMed:16033761, ECO:0000269\|PubMed:23109336, ECO:0000269\|PubMed:27084579, ECO:0000269\|PubMed:27302062}. Late endosome {ECO:0000269\|PubMed:16033761, ECO:0000269\|PubMed:23109336, ECO:0000269\|PubMed:27084579, ECO:0000269\|PubMed:27302062}. Early endosome {ECO:0000269\|PubMed:15615712, ECO:0000269\|PubMed:15886016, ECO:0000269\|PubMed:23109336, ECO:0000269\|PubMed:27084579, ECO:0000269\|PubMed:27302062}. Recycling endosome {ECO:0000269\|PubMed:15886016, ECO:0000269\|PubMed:27084579, ECO:0000269\|PubMed:27302062}. Cell projection, axon {ECO:0000250\|UniProtKB:P56818}. Cell projection, dendrite {ECO:0000250\|UniProtKB:P56818}. Note=Predominantly localized to the later Golgi/trans-Golgi network (TGN) and minimally detectable in the early Golgi compartments. A small portion is also found in the endoplasmic reticulum, endosomes and on the cell surface (PubMed:17425515, PubMed:11466313). Colocalization with APP in early endosomes is due to addition of bisecting N-acetylglucosamine wich blocks targeting to late endosomes and lysosomes (By similarity). Retrogradly transported from endosomal compartments to the trans-Golgi network in a phosphorylation- and GGA1- dependent manner (PubMed:15886016). {ECO:0000250\|UniProtKB:P56818, ECO:0000269\|PubMed:11466313, ECO:0000269\|PubMed:15886016, ECO:0000269\|PubMed:17425515}.
Tissue specificity:		Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata. {ECO:0000269\|PubMed:10677483, ECO:0000269\|PubMed:11083922}.
Induction:		Up-regulated by the Ca(2+)-regulated transcription factor NFATC4. {ECO:0000269\|PubMed:25663301}.
Domain:		DXXLL motif is required for a proper endocytosis and retrograde transport to the trans-Golgi network, as well as for regulation of lysosomal degradation. {ECO:0000269\|PubMed:23109336}.
Domain:		The transmembrane domain is necessary for its activity. It determines its late Golgi localization and access to its substrate, APP. {ECO:0000269\|PubMed:11466313}.
Ptm:		N-Glycosylated (PubMed:11083922, PubMed:17425515). Addition of a bisecting N-acetylglucosamine by MGAT3 blocks lysosomal targeting, further degradation and is required for maintaining stability under stress conditions (By similarity). {ECO:0000250\|UniProtKB:P56818, ECO:0000269\|PubMed:11083922, ECO:0000269\|PubMed:17425515}.
Ptm:		Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys- 279, Lys-285, Lys-299, Lys-300 and Lys-307. Acetylation by NAT8 and NAT8B is transient and deacetylation probably occurs in the Golgi. Acetylation regulates the maturation, the transport to the plasma membrane, the stability and the expression of the protein. {ECO:0000269\|PubMed:17425515, ECO:0000269\|PubMed:19011241}.
Ptm:		Palmitoylation mediates lipid raft localization. {ECO:0000250\|UniProtKB:P56818}.
Ptm:		Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation (PubMed:27302062, PubMed:16033761, PubMed:20484053, PubMed:23109336). Monoubiquitinated and 'Lys-63'-linked polyubitinated (PubMed:20484053). Deubiquitnated by USP8; inhibits lysosomal degradation (PubMed:27302062). {ECO:0000269\|PubMed:16033761, ECO:0000269\|PubMed:20484053, ECO:0000269\|PubMed:23109336, ECO:0000269\|PubMed:27302062}.
Ptm:		Phosphorylation at Ser-498 is required for interaction with GGA1 and retrograded transport from endosomal compartments to the trans- Golgi network. Non-phosphorylated BACE1 enters a direct recycling route to the cell surface. {ECO:0000269\|PubMed:15886016}.
Similarity:		Belongs to the peptidase A1 family. {ECO:0000305}.
Sequence caution:		Sequence=BAA86463.2; Type=Frameshift; Evidence={ECO:0000305};