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Annular anionic lipids stabilize the integrin αIIbβ3 transmembrane complex

Thomas Schmidt1, Jae-Eun Suk1, Feng Ye2

  • 1From the Department of Biochemistry & Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and.

The Journal of Biological Chemistry
|January 31, 2015
PubMed

Cationic membrane-proximal amino acids determine the topology of membrane proteins by interacting with anionic lipids that are restricted to the intracellular membrane leaflet. This mechanism implies that anionic lipids interfere with electrostatic interactions of membrane proteins. The integrin αIIbβ3 transmembrane (TM) complex is stabilized by a membrane-proximal αIIb(Arg(995))-β3(Asp(723)) interaction; here, we examine the influence of anionic lipids on this complex. Anionic lipids compete for αIIb(Arg(995)) contacts with β3(Asp(723)) but paradoxically do not diminish the contribution of αIIb(Arg(995))-β3(Asp(723)) to TM complex stability. Overall, anionic lipids in annular positions stabilize the αIIbβ3 TM complex by up to 0.50 ± 0.02 kcal/mol relative to zwitterionic lipids in a headgroup structure-dependent manner. Comparatively, integrin receptor activation requires TM complex destabilization of 1.5 ± 0.2 kcal/mol, revealing a sizeable influence of lipid composition on TM complex stability. We implicate changes in lipid headgroup accessibility to small molecules (physical membrane characteristics) and specific but dynamic protein-lipid contacts in this TM helix-helix stabilization. Thus, anionic lipids in ubiquitous annular positions can benefit the stability of membrane proteins while leaving membrane-proximal electrostatic interactions intact.

Keywords:
BiophysicsIntegrinMembrane LipidMembrane ProteinMolecular DynamicsNuclear Magnetic Resonance (NMR)Protein-Lipid Interaction

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