Literature summary for 3.4.21.61 extracted from

Geschwindner, S.; Andersson, G.M.; Beisel, H.G.; Breuer, S.; Hallberg, C.; Kihlberg, B.M.; Lindqvist, A.M.; OMahony, G.; Plowright, A.T.; Raubacher, F.; Knecht, W.
Characterisation of de novo mutations in the C-terminal domain of proprotein convertase subtilisin/kexin type 9 (2015), Protein Eng. Des. Sel., 2015, 1-9.

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Application

Application	Comment	Organism
medicine	the enzyme is a prominent therapeutic target for reducing LDL-cholesterol	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression of enzyme mutants in Hep-G2 cells	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
D374Y	a naturally occurring gain-of-function mutation causing severe hypercholesterolaemia in humans due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant	Homo sapiens
E569K	site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens
G517R	site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens
additional information	analysis of the importance of the enzyme's C-terminus in degradation of the LDL-receptor by designing seven de novomutants of PCSK9 that fill potential druggable cavities	Homo sapiens
R659A	site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens
R659E	site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens
S636R	site-directed mutagenesis, the mutant shows slightly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens
V610R	site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens
V644R	site-directed mutagenesis, the mutant shows highly decreased ability to block LDL uptake into HepG2 cells compared to the wild-type enzyme	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
additional information	areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
low density lipoprotein receptor + H2O	Homo sapiens	degradation	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q8NBP7	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
low density lipoprotein receptor + H2O	degradation	Homo sapiens	?	-	?

Subunits

Subunits	Comment	Organism
More	the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain	Homo sapiens

Synonyms

Synonyms	Comment	Organism
PCSK9	-	Homo sapiens
proprotein convertase subtilisin/kexin type 9	-	Homo sapiens

General Information

General Information	Comment	Organism
malfunction	D374Y is a naturally occurring gain-of-function mutation causing severe hypercholesterolaemia in humans due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant	Homo sapiens
additional information	the enzyme contains a signal peptide and a prodomain followed by a catalytic protease domain, a hinge-region and a C-terminal domain. Areas outside the direct interaction area between PCSK9 and the LDL-R can be targeted to inhibit the PCSK9 triggered degradation of the LDL-receptor, Equilibrium binding parameters for the interaction between the LDL-R ectodomain and wt PCSK9 as well as PCSK9 mutants determined by surface plasmon resonance at 25°C, steady-state analysis and kinetic analysis, overview	Homo sapiens
physiological function	the enzyme promotes the degradation of the hepatic low density lipoprotein receptor. The C-terminal domain of the enzyme is unlikely to be involved in a direct extracellular interaction with the LDL-receptor	Homo sapiens

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Release 2023.1 (January 2023)