Document Detail

Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events.
MedLine Citation:
PMID:  20937814     Owner:  NLM     Status:  MEDLINE    
PCSK9, a target for the treatment of dyslipidemia, enhances the degradation of the LDL receptor (LDLR) in endosomes/lysosomes, up-regulating LDL-cholesterol levels. Whereas the targeting and degradation of the PCSK9-LDLR complex are under scrutiny, the roles of the N- and C-terminal domains of PCSK9 are unknown. Although autocatalytic zymogen processing of PCSK9 occurs at Gln(152)↓, here we show that human PCSK9 can be further cleaved in its N-terminal prosegment at Arg(46)↓ by an endogenous enzyme of insect High Five cells and by a cellular mammalian protease, yielding an ∼4-fold enhanced activity. Removal of the prosegment acidic stretch resulted in ∼3-fold higher binding to LDLR in vitro, in ≥4-fold increased activity on cellular LDLR, and faster cellular internalization in endosome/lysosome-like compartments. Finally, swapping the acidic stretch of PCSK9 with a similar one found in the glycosylphosphatidylinositol-anchored heparin-binding protein 1 does not impair PCSK9 autoprocessing, secretion, or activity and confirmed that the acidic stretch acts as an inhibitor of PCSK9 function. We also show that upon short exposure to pH values 6.5 to 5.5, an ∼2.5-fold increase in PCSK9 activity on total and cell surface LDLR occurs, and PCSK9 undergoes a second cleavage at Arg(248), generating a two-chain PCSK9-ΔN(248). At pH values below 5.5, PCSK9 dissociates from its prosegment and loses its activity. This pH-dependent activation of PCSK9 represents a novel pathway to further activate PCSK9 in acidic endosomes. These data enhance our understanding of the functional role of the acidic prosegment and on the effect of pH in the regulation of PCSK9 activity.
Suzanne Benjannet; Yascara Grisel Luna Saavedra; Josée Hamelin; Marie-Claude Asselin; Rachid Essalmani; Antonella Pasquato; Peter Lemaire; Gerald Duke; Bowman Miao; Franck Duclos; Rex Parker; Gaétan Mayer; Nabil G Seidah
Related Documents :
27504 - Use of fluorescamine-labeled casein as a substrate for assay of proteinases.
16820854 - Reactivity of halides with triplets of 6-chloro and 6-bromopicolinic acids: contrasting...
5184 - Acid proteases from species of mucor. iv. hydrogen-tritium exchange of mucor miehei pro...
19631464 - Assessment of the biosorption characteristics of a macro-fungus for the decolorization ...
14342244 - The respiration of isolated rat-hepatic cells in suspension.
7410334 - Regulation of cell wall mycolic acid biosynthesis in acid-fast bacteria. i. temperature...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-11
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-20     Completed Date:  2011-01-24     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  40965-78     Citation Subset:  IM    
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Endosomes / enzymology*,  genetics
Enzyme Activation / physiology
HEK293 Cells
Hep G2 Cells
Hydrogen-Ion Concentration
Lysosomes / enzymology,  genetics
Peptides / genetics,  metabolism*
Proprotein Convertases
Protein Binding / physiology
Protein Processing, Post-Translational / physiology*
Receptors, LDL / genetics,  metabolism*
Serine Endopeptidases / genetics,  metabolism*
Grant Support
MOP-102741//Canadian Institutes of Health Research
Reg. No./Substance:
0/Peptides; 0/Receptors, LDL; EC 3.4.-/Proprotein Convertases; EC 3.4.21.-/PCSK9 protein, human; EC 3.4.21.-/Serine Endopeptidases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Identification and functions of amino acid residues in PotB and PotC involved in spermidine uptake a...
Next Document:  Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and ...