Insight into signal transduction: structural alterations in transmembrane helices probed by multi-1 ns molecular dynamics simulations

Journal of Biomolecular Structure & Dynamics
J P DuneauM Genest

Abstract

The hypothesis of structural alteration in transmembrane helices for signal transduction process is viewed by molecular dynamics simulation techniques. For the c-erbB-2 transmembrane domain involved in oncogenicity, the occurrence of conformational changes has been previously described as transition from the alpha to pi helix. This dynamical feature is thoroughly analyzed for the wild phenotype and oncogenic sequences from a series of 18 simulations carried out on one nanosecond time scale. We show that these structural events do not depend upon the conditions of simulations like force field or starting helix coordinates. We demonstrate that the oncogenic mutations Val659 Glu, Gln and Asp do not prevent the transition. Furthermore, we show that beta branched residues, in conjunction with Gly residues in the c-erbB-2 sequence, act as destabilizers for the alpha helix structure, pi deformations are tightly related to other local structural motifs found in soluble and membrane proteins. These structural alterations are discussed in term of structure-activity relationships for the c-erbB-2 activating mechanism mediated by transmembrane domain dimerization.

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Citations

Jun 19, 2001·Current Opinion in Structural Biology·I Ubarretxena-Belandia, D M Engelman
Jun 16, 2004·European Biophysics Journal : EBJ·Bryan M van der EndeJames H Davis
Jan 27, 2005·Journal of Molecular Graphics & Modelling·Jaime Arce LoperaJean-Pierre Duneau
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Apr 16, 2013·Biochimie·Jaroslav KubrychtJiří Hudeček
Aug 18, 2009·Chemistry and Physics of Lipids·Natalie Bordag, Sandro Keller
Sep 6, 2003·Journal of Biomolecular Structure & Dynamics·Norbert GarnierMonique Genest
Oct 24, 2006·Journal of Biomolecular Structure & Dynamics·Pierre AllerMonique Genest
Mar 31, 2004·The Journal of Biological Chemistry·R Scott HoulistonJames H Davis

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