N-Ras Forms Dimers at POPC Membranes

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2012 Oct 16

PMID 23062351

Citations 87

Authors

Jorn Guldenhaupt

Till Rudack

Peter Bachler

Daniel Mann

Gemma Triola

Herbert Waldmann

Carsten Kotting

Klaus Gerwert

Affiliations

Soon will be listed here.

Abstract

Ras is a central regulator of cellular signaling pathways. It is mutated in 20-30% of human tumors. To perform its function, Ras has to be bound to a membrane by a posttranslationally attached lipid anchor. Surprisingly, we identified here dimerization of membrane anchored Ras by combining attenuated total reflectance Fourier transform infrared spectroscopy, biomolecular simulations, and Förster resonance energy transfer experiments. By analyzing x-ray structural models and molecular-dynamics simulations, we propose a dimerization interface between α-helices 4 and 5 and the loop between β2 and β3. This seems to explain why the residues D47, E49, R135, R161, and R164 of this interface are influencing Ras signaling in cellular physiological experiments, although they are not positioned in the catalytic site. Dimerization could catalyze nanoclustering, which is well accepted for membrane-bound Ras. The interface could provide a new target for a seemingly novel type of small molecule interfering with signal transduction in oncogenic Ras mutants.

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