Literature summary for 3.4.21.61 extracted from

Chorba, J.S.; Shokat, K.M.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) active site and cleavage sequence differentially regulate protein secretion from proteolysis (2014), J. Biol. Chem., 289, 29030-29043.

Search for more literature for 3.4.21.61

Application

Application	Comment	Organism
drug development	the enzyme is a target for to drug development for inhibiting the PCSK9 processing pathway and ultimately disrupt the interaction with the LDL receptor, strategy for intracellular enzyme inhibition	Homo sapiens
medicine	biologic-based strategies to inhibit proprotein convertase subtilisin/kexin type 9 show promise as anti-hypercholesterolemic and, therefore, anti-atherosclerotic therapies	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant His-tagged enzyme catalytic domain expression in HEK-293T cells and secretion to the medium	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
additional information	a secretion-defective PCSK9 mutant can transfer its prodomain to a prodomain-deficient (and also secretion-defective) enzyme, rescuing the secretion of the latter enzyme species	Homo sapiens
Q152H	a dominant negative mutation that restricts enzyme proteolysis and secretion independently	Homo sapiens
Q152I	te mutation completely abrogates proteolysis in both intra- and intermolecular systems but has only a limited impact on secretion	Homo sapiens
Q152R	the mutation completely abolished both proteolysis and secretion	Homo sapiens
Q152X	four phenotypes of Q152X mutants, overview	Homo sapiens
S386A	inactive mutant	Homo sapiens
V149A	the mutant shows intolerance for intermolecular cleavage of the enzyme, residue Val149 is critical for secretion	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
extracellular	the enzyme's prodomain inhibits intermolecular proteolysis in trans and requires the C-terminus for full inhibition and proper secretion, residue Val149 is critical for secretion	Homo sapiens	-	-
additional information	residues of the prodomain C-terminus regulate proteolysis and secretion independently	Homo sapiens	-	-

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q8NBP7	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
proteolytic modification	conversion of wild-type proPCSK9 to mature PCSK9 occurs in an intramolecular fashion, but the prodomain and catalytic domain can be assembled in trans (i.e. as two separate polypeptides), which effectively bypasses the need for proteolysis and does not require intrinsic proteolytic activity	Homo sapiens

Purification (Commentary)

Purification (Comment)	Organism
recombinant His-tagged enzyme from HEK-293T cell medium by nickel affinity chromatography	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	the enzyme catalytic domain is capable of proteolysis in trans (i.e. as two separate polypeptides), and can perform intermolecular proteolysis	Homo sapiens	?	-	?

Synonyms

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

General Information

General Information	Comment	Organism
additional information	differential structural requirements of the proteolytic site and requirements for secretion in trans in a system that effectively bypasses the need for proteolysis, overview. The enzyme's prodomain inhibits intermolecular proteolysis in trans and requires the C-terminus for full inhibition and proper secretion. the enzyme's active site and its adjacent residues serve as an allosteric modulator of protein secretion independent of its role in proteolysis, specific residues in the protease recognition sequence can differentially modulate the effects on proteolysis and secretion	Homo sapiens
physiological function	residues of the prodomain C-terminus regulate proteolysis and secretion independently. The prodomain C-terminus regulates protein secretion but is not required for catalytic domain binding	Homo sapiens

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Release 2023.1 (January 2023)