InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Pcsk9

Summary

InnateDB Protein

IDBP-170190.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

Pcsk9

Protein Name

proprotein convertase subtilisin/kexin type 9

Synonyms

AI415265; AI747682; FH3; HCHOLA3; Narc1; PC9;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000055757

InnateDB Gene

IDBG-170186 (Pcsk9)

Protein Structure

UniProt Annotation

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. 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. 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. 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:0000269PubMed:22481440, ECO:0000269PubMed:22580899}.

Subcellular Localization

Cytoplasm {ECO:0000250}. Secreted. Endosome {ECO:0000250}. Lysosome {ECO:0000250}. Cell surface {ECO:0000250}. Endoplasmic reticulum {ECO:0000250}. Golgi apparatus {ECO:0000250}. 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 co-localizes 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 (By similarity). {ECO:0000250}.

Disease Associations

Tissue Specificity

Hepatocytes, kidney mesenchymal cells, intestinal ileum, colon epithelia and embryonic brain telencephalon neurons.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 0 experimentally validated interaction(s) in this database.
They are also associated with 3 interaction(s) predicted by orthology.

Predicted by orthology
Total	3 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004252	serine-type endopeptidase activity
GO:0005515	protein binding
GO:0019871	sodium channel inhibitor activity
GO:0030169	low-density lipoprotein particle binding
GO:0034185	apolipoprotein binding
GO:0034189	very-low-density lipoprotein particle binding
GO:0034190	apolipoprotein receptor binding
GO:0043621	protein self-association
GO:0044822	poly(A) RNA binding
GO:0050750	low-density lipoprotein particle receptor binding
GO:0070326	very-low-density lipoprotein particle receptor binding

Biological Process

GO:0001822	kidney development
GO:0001889	liver development
GO:0001920	negative regulation of receptor recycling
GO:0002092	positive regulation of receptor internalization
GO:0006508	proteolysis
GO:0006641	triglyceride metabolic process
GO:0006644	phospholipid metabolic process
GO:0006915	apoptotic process
GO:0007041	lysosomal transport
GO:0008203	cholesterol metabolic process
GO:0009267	cellular response to starvation
GO:0010469	regulation of receptor activity
GO:0010989	negative regulation of low-density lipoprotein particle clearance
GO:0016485	protein processing
GO:0016540	protein autoprocessing
GO:0022008	neurogenesis
GO:0030182	neuron differentiation
GO:0032799	low-density lipoprotein receptor particle metabolic process
GO:0032802	low-density lipoprotein particle receptor catabolic process
GO:0032803	regulation of low-density lipoprotein particle receptor catabolic process
GO:0032869	cellular response to insulin stimulus
GO:0042157	lipoprotein metabolic process
GO:0042632	cholesterol homeostasis
GO:0043523	regulation of neuron apoptotic process
GO:0043525	positive regulation of neuron apoptotic process

Cellular Component

GO:0005576	extracellular region
GO:0005615	extracellular space
GO:0005737	cytoplasm
GO:0005764	lysosome
GO:0005769	early endosome
GO:0005770	late endosome
GO:0005783	endoplasmic reticulum
GO:0005788	endoplasmic reticulum lumen
GO:0005791	rough endoplasmic reticulum
GO:0005794	Golgi apparatus
GO:0005886	plasma membrane
GO:0009986	cell surface
GO:0030134	ER to Golgi transport vesicle
GO:0048471	perinuclear region of cytoplasm

Protein Structure and Domains

PDB ID

MGI:2140260

InterPro

IPR000209 Peptidase S8/S53 domain
IPR009020 Proteinase inhibitor, propeptide
IPR010259 Proteinase inhibitor I9
IPR015500 Peptidase S8, subtilisin-related

PFAM

PF00082
PF05922

PRINTS

PR00723

PIRSF

SMART

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt

Q80W65