UniProt functional annotation for Q8NBP7



	UniProt functional annotation for Q8NBP7

UniProt code: Q8NBP7.

Organism: Homo sapiens (Human).

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

Function: Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PubMed:18039658). Acts via a non- proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. {ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658, ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:22074827, ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899}.

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000305};

Activity regulation: Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.

Subunit: Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR (PubMed:18799458). {ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658, ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:21149300, ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899, ECO:0000269|PubMed:24808179}.

Subcellular location: Cytoplasm. Secreted. Endosome. Lysosome. Cell surface. Endoplasmic reticulum. Golgi apparatus. Note=Autocatalytic cleavage is required to transport it from the endoplasmic reticulum to the Golgi apparatus and for the secretion of the mature protein. Localizes to the endoplasmic reticulum in the absence of LDLR and colocalizes to the cell surface and to the endosomes/lysosomes in the presence of LDLR. The sorting to the cell surface and endosomes is required in order to fully promote LDLR degradation.

Tissue specificity: Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.

Domain: The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities. {ECO:0000269|PubMed:22027821}.

Domain: The catalytic domain is responsible for mediating its self- association. {ECO:0000269|PubMed:22027821}.

Ptm: Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. {ECO:0000269|PubMed:16912035}.

Ptm: Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The cleaved propeptide however remains associated with the catalytic domain through non-covalent interactions, preventing potential substrates from accessing its active site. As a result, it is secreted from cells as a propeptide-containing, enzymatically inactive protein. {ECO:0000269|PubMed:14622975}.

Ptm: Phosphorylation protects the propeptide against proteolysis. {ECO:0000269|PubMed:18498363}.

Polymorphism: Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia.

Polymorphism: Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776]. {ECO:0000269|PubMed:19319977, ECO:0000269|PubMed:22095935, ECO:0000269|PubMed:22417841}.

Disease: Hypercholesterolemia, familial, 3 (FHCL3) [MIM:603776]: A form of hypercholesterolemia, a disorder of lipoprotein metabolism characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. FHCL3 inheritance is autosomal dominant. {ECO:0000269|PubMed:12730697, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:24808179}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the peptidase S8 family. {ECO:0000305}.

Sequence caution: Sequence=BAC11572.1; 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:		Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PubMed:18039658). Acts via a non- proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. {ECO:0000269\|PubMed:17461796, ECO:0000269\|PubMed:18039658, ECO:0000269\|PubMed:18197702, ECO:0000269\|PubMed:18660751, ECO:0000269\|PubMed:18799458, ECO:0000269\|PubMed:22074827, ECO:0000269\|PubMed:22493497, ECO:0000269\|PubMed:22580899}.


Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000305};
Activity regulation:		Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.
Subunit:		Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR (PubMed:18799458). {ECO:0000269\|PubMed:17461796, ECO:0000269\|PubMed:18039658, ECO:0000269\|PubMed:18197702, ECO:0000269\|PubMed:18660751, ECO:0000269\|PubMed:18799458, ECO:0000269\|PubMed:21149300, ECO:0000269\|PubMed:22493497, ECO:0000269\|PubMed:22580899, ECO:0000269\|PubMed:24808179}.
Subcellular location:		Cytoplasm. Secreted. Endosome. Lysosome. Cell surface. Endoplasmic reticulum. Golgi apparatus. Note=Autocatalytic cleavage is required to transport it from the endoplasmic reticulum to the Golgi apparatus and for the secretion of the mature protein. Localizes to the endoplasmic reticulum in the absence of LDLR and colocalizes to the cell surface and to the endosomes/lysosomes in the presence of LDLR. The sorting to the cell surface and endosomes is required in order to fully promote LDLR degradation.
Tissue specificity:		Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.
Domain:		The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities. {ECO:0000269\|PubMed:22027821}.
Domain:		The catalytic domain is responsible for mediating its self- association. {ECO:0000269\|PubMed:22027821}.
Ptm:		Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. {ECO:0000269\|PubMed:16912035}.
Ptm:		Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The cleaved propeptide however remains associated with the catalytic domain through non-covalent interactions, preventing potential substrates from accessing its active site. As a result, it is secreted from cells as a propeptide-containing, enzymatically inactive protein. {ECO:0000269\|PubMed:14622975}.
Ptm:		Phosphorylation protects the propeptide against proteolysis. {ECO:0000269\|PubMed:18498363}.
Polymorphism:		Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia.
Polymorphism:		Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776]. {ECO:0000269\|PubMed:19319977, ECO:0000269\|PubMed:22095935, ECO:0000269\|PubMed:22417841}.
Disease:		Hypercholesterolemia, familial, 3 (FHCL3) [MIM:603776]: A form of hypercholesterolemia, a disorder of lipoprotein metabolism characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. FHCL3 inheritance is autosomal dominant. {ECO:0000269\|PubMed:12730697, ECO:0000269\|PubMed:18799458, ECO:0000269\|PubMed:24808179}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the peptidase S8 family. {ECO:0000305}.
Sequence caution:		Sequence=BAC11572.1; Type=Frameshift; Evidence={ECO:0000305};