Document Detail

Atomistic molecular dynamics simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP.
MedLine Citation:
PMID:  25424006     Owner:  NLM     Status:  Publisher    
Inhibition of CETP, a protein mediating transfer of neutral lipids between lipoproteins, has been proposed as a means to elevate atheroprotective HDL subpopulations and thereby reduce atherosclerosis. However, off-target and adverse effects of the inhibition have raised doubts about the molecular mechanism of CETP-HDL interaction. Recent experimental findings have demonstrated the penetration of CETP into HDL. However, atomic level resolution of CETP penetration into HDL, a prerequisite for a better understanding of CETP functionality and HDL atheroprotection, is missing. We constructed an HDL particle mimicking the actual human HDL mass composition and investigated for the first time by large-scale atomistic molecular dynamics the interaction of an upright CETP with a human HDL mimicking model. The results demonstrated how CETP can penetrate HDL particle surface, with the formation of an opening in the N barrel domain end of CETP, put in evidence the major anchoring role of a tryptophan-rich region of this domain, and unveiled the presence of a phenylalanine barrier controlling further access of HDL-derived lipids to the tunnel of CETP. The findings reveal novel atomistic details of CETP-HDL interaction mechanism and can provide new insight into therapeutic strategies.
Geraldine Cilpa-Karhu; Matti Jauhiainen; Marja-Liisa Riekkola
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-25
Journal Detail:
Title:  Journal of lipid research     Volume:  -     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-26     Completed Date:  -     Revised Date:  2014-11-27    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
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