Document Detail

Influence of C-terminal α-helix hydrophobicity and aromatic amino acid content on apolipoprotein A-I functionality.
MedLine Citation:
PMID:  21840419     Owner:  NLM     Status:  MEDLINE    
The apoA-I molecule adopts a two-domain tertiary structure and the properties of these domains modulate the ability to form HDL particles. Thus, human apoA-I differs from mouse apoA-I in that it can form smaller HDL particles; the C-terminal α-helix is important in this process and human apoA-I is unusual in containing aromatic amino acids in the non-polar face of this amphipathic α-helix. To understand the influence of these aromatic amino acids and the associated high hydrophobicity, apoA-I variants were engineered in which aliphatic amino acids were substituted with or without causing a decrease in overall hydrophobicity. The variants human apoA-I (F225L/F229A/Y236A) and apoA-I (F225L/F229L/A232L/Y236L) were compared to wild-type (WT) apoA-I for their abilities to (1) solubilize phospholipid vesicles and form HDL particles of different sizes, and (2) mediate cellular cholesterol efflux and create nascent HDL particles via ABCA1. The loss of aromatic residues and concomitant decrease in hydrophobicity in apoA-I (F225L/F229A/Y236A) has no effect on protein stability, but reduces by a factor of about three the catalytic efficiencies (V(max)/K(m)) of vesicle solubilization and cholesterol efflux; also, relatively large HDL particles are formed. With apoA-I (F225L/F229L/A232L/Y236L) where the hydrophobicity is restored by the presence of only leucine residues in the helix non-polar face, the catalytic efficiencies of vesicle solubilization and cholesterol efflux are similar to those of WT apoA-I; this variant forms smaller HDL particles. Overall, the results show that the hydrophobicity of the non-polar face of the C-terminal amphipathic α-helix plays a critical role in determining apoA-I functionality but aromatic amino acids are not required. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
Nicholas N Lyssenko; Mami Hata; Padmaja Dhanasekaran; Margaret Nickel; David Nguyen; Palaniappan Sevugan Chetty; Hiroyuki Saito; Sissel Lund-Katz; Michael C Phillips
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-05
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1821     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-27     Completed Date:  2012-11-26     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  456-63     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier B.V. All rights reserved.
Lipid Research Group, Gastroenterology, Hepatology and Nutrition Division, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA.
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MeSH Terms
ATP-Binding Cassette Transporters / metabolism
Amino Acid Substitution
Amino Acids, Aromatic / chemistry*
Apolipoprotein A-I / chemistry*,  genetics,  metabolism
Cells, Cultured
Cholesterol / metabolism
Hydrophobic and Hydrophilic Interactions
Lipoproteins, HDL / metabolism*
Mutagenesis, Site-Directed
Protein Denaturation
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Transition Temperature
Grant Support
Reg. No./Substance:
0/APOA1 protein, human; 0/ATP binding cassette transporter 1; 0/Amino Acids, Aromatic; 0/Apolipoprotein A-I; 0/Lipoproteins, HDL; 57-88-5/Cholesterol

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