The role of hydrophobic and negatively charged surface patches of lipid-free apolipoprotein A-I in lipid binding and ABCA1-mediated cholesterol efflux

Loren E Smith; W Sean Davidson

doi:10.1016/j.bbalip.2009.09.012

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The role of hydrophobic and negatively charged surface patches of lipid-free apolipoprotein A-I in lipid binding and ABCA1-mediated cholesterol efflux

Journal article

Peer reviewed

The role of hydrophobic and negatively charged surface patches of lipid-free apolipoprotein A-I in lipid binding and ABCA1-mediated cholesterol efflux

Loren E Smith and W Sean Davidson

Biochimica et biophysica acta, Vol.1801(1), pp.64-69

01/01/2010

DOI: 10.1016/j.bbalip.2009.09.012

PMCID: PMC2787660

PMID: 19782154

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Abstract

Recent models of lipid-free apolipoprotein A-I, including a cross-link/homology model and an X-ray crystal structure have identified two potential functionally relevant "patches" on the protein surface. The first is a hydrophobic surface patch composed of leucine residues 42, 44, 46, and 47 and the second a negatively charged patch composed of glutamic acid residues 179, 191, and 198. To determine if these domains play a functional role, these surface patches were disrupted by site-directed mutagenesis and the bacterially expressed mutants were compared with respect to their ability to bind lipid and stimulate ABCA1-mediated cholesterol efflux. It was found that neither patch plays a significant functional role in the ability of apoA-I to accept cholesterol in an ABCA1-dependent manner, but that the hydrophobic patch did affect the ability of apoA-I to clear DMPC liposomes. Interestingly, contrary to previous predictions, disruption of the hydrophobic surface patch enhanced the lipid binding ability of apoA-I. The hydrophobic surface patch may be important to the structural stability of lipid-free apoA-I or may be a necessary permissive structural element for lipid binding.

Apolipoprotein A-I - chemistry

Apolipoprotein A-I - genetics

Apolipoprotein A-I - metabolism

ATP Binding Cassette Transporter 1

ATP-Binding Cassette Transporters - metabolism

Binding Sites

Biological Transport

Cholesterol - metabolism

Crystallography, X-Ray

Hydrophobic and Hydrophilic Interactions

Lipid Metabolism

Mutagenesis, Site-Directed

Protein Conformation

Structure-Activity Relationship

Details

Title: Subtitle: The role of hydrophobic and negatively charged surface patches of lipid-free apolipoprotein A-I in lipid binding and ABCA1-mediated cholesterol efflux
Creators: Loren E Smith - University of Cincinnati
W Sean Davidson - University of Cincinnati
Resource Type: Journal article
Publication Details: Biochimica et biophysica acta, Vol.1801(1), pp.64-69
DOI: 10.1016/j.bbalip.2009.09.012
PMID: 19782154
PMCID: PMC2787660
NLM abbreviation: Biochim Biophys Acta Mol Cell Biol Lipids
ISSN: 0006-3002
eISSN: 1879-2618
Grant note: R01 HL062542 / NHLBI NIH HHS HL67093 / NHLBI NIH HHS R01 HL067093 / NHLBI NIH HHS
Language: English
Date published: 01/01/2010
Academic Unit: Anesthesia
Record Identifier: 9984949263102771

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