Membrane-sensitive conformational states of helix 8 in the metabotropic Glu2 receptor, a class C GPCR

PLoS One. 2012;7(8):e42023. doi: 10.1371/journal.pone.0042023. Epub 2012 Aug 1.

Abstract

The recent elucidation of the X-ray structure of several class A GPCRs clearly indicates that the amphipathic helix 8 (H8) is a conserved structural domain in most crystallized GPCRs. Very little is known about the presence and the possible role of an analogous H8 domain in the distantly related class C GPCRs. In this study, we investigated the structural properties for the H8 domain of the mGluR2 receptor, a class C GPCR, by applying extended molecular dynamics simulations. Our study indicates that the amphipathic H8 adopts membrane-sensitive conformational states, which depend on the membrane composition. Cholesterol-rich membranes stabilize the helical structure of H8 whereas cholesterol-depleted membranes induce a disruption of H8. The observed link between membrane cholesterol levels and H8 conformational states suggests that H8 behaves as a sensor of cholesterol concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / genetics*
  • Cell Membrane / metabolism
  • Cholesterol / chemistry*
  • Cholesterol / metabolism
  • Crystallography, X-Ray
  • Humans
  • Molecular Dynamics Simulation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism

Substances

  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Cholesterol

Grants and funding

The authors gratefully acknowledge financial support from La MARATO de TV3 Foundation (Ref.-No. 091010) and the Spanish Ministerio de Educación y Ciencia (SAF2009-13609-C04-04). GC and AB gratefully acknowledge the CINECA consortium for the support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.