Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein

Charles Wilson, Ted Mau, Karl H. Weisgraber, Mark R. Wardell, Robert W. Mahley, David A. Agard

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Background Apolipoprotein-E (apo-E), a 34kDa blood plasma protein, plays a key role in directing cholesterol transport via its interaction with the low density lipoprotein (LDL) receptor. The amino-terminal domain of apo-E forms an unusually elongated four-helix bundle arranged such that key basic residues involved in LDL receptor binding form a cluster at the end of one of the helices. A common apo-E variant, apo-E2, corresponding to the single-site substitution Arg158→Cys, displays minimal LDL receptor binding and is associated with significant changes in plasma cholesterol levels and increased risk of coronary heart disease. Surprisingly, the site of mutation in this variant is physically well removed (>12å) from the cluster of LDL receptor binding residues. Results We now report the refined crystal structure of the amino-terminal domain of apo-E2, at a nominal resolution of 3.0å. This structure reveals significant conformational changes relative to the wild-type protein that may account for reduced LDL receptor binding. Removal of the Arg158 side chain directly disrupts a pair of salt bridges, causing a compensatory reorganization of salt bridge partners that dramatically alters the charge surface presented by apo-E to its receptor. Conclusions It is proposed that the observed reorganization of surface salt bridges is responsible for the decreased receptor binding by apo-E2. This reorganization, essentially functioning as a mutationally-induced electrostatic switch to turn off receptor binding, represents a novel mechanism for the propagation of conformational changes over significant distances.

Original languageEnglish (US)
Pages (from-to)713-718
Number of pages6
JournalStructure
Volume2
Issue number8
DOIs
StatePublished - Aug 1994

Keywords

  • LDL receptor
  • apolipoprotein
  • cholesterol metabolism
  • electrostatic switch

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Wilson, C., Mau, T., Weisgraber, K. H., Wardell, M. R., Mahley, R. W., & Agard, D. A. (1994). Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure, 2(8), 713-718. https://doi.org/10.1016/S0969-2126(00)00072-1