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J Lipid Res. 2014 Sep;55(9):1876-85. doi: 10.1194/jlr.M047241. Epub 2014 Jun 11.

Binding of human apoA-I[K107del] variant to TG-rich particles: implications for mechanisms underlying hypertriglyceridemia.

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  • 1Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118 Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
  • 2Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118.

Abstract

We found earlier that apoA-I variants that induced hypertriglyceridemia (HTG) in mice had increased affinity to TG-rich lipoproteins and thereby impaired their catabolism. Here, we tested whether a naturally occurring human apoA-I mutation, Lys107del, associated with HTG also promotes apoA-I binding to TG-rich particles. We expressed apoA-I[Lys107del] variant in Escherichia coli, studied its binding to TG-rich emulsion particles, and performed a physicochemical characterization of the protein. Compared with WT apoA-I, apoA-I[Lys107del] showed enhanced binding to TG-rich particles, lower stability, and greater exposure of hydrophobic surfaces. The crystal structure of truncated, Δ(185-243), apoA-I suggests that deletion of Lys107 disrupts helix registration and disturbs a stabilizing salt bridge network in the N-terminal helical bundle. To elucidate the structural changes responsible for the altered function of apoA-I[Lys107del], we studied another mutant, apoA-I [Lys107Ala]. Our findings suggest that the registry shift and ensuing disruption of the inter-helical salt bridges in apoA-I[Lys107del] result in destabilization of the helical bundle structure and greater exposure of hydrophobic surfaces. We conclude that the structural changes in the apoA-I[Lys107del] variant facilitate its binding to TG-rich lipoproteins and thus, may reduce their lipolysis and contribute to the development of HTG in carriers of the mutation.

Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

apolipoprotein A-I; high plasma triglyceride levels; natural mutation; triglyceride; very low density lipoprotein

PMID:
24919401
[PubMed - in process]
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