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Protein Interactions and Membrane Geometry

Michael Grabe^*, John Neu, George Oster and Peter Nollert

^* Department of Physics, Department of Mathematics, and Department of Molecular and Cellular Biology and College of Natural Resources, University of California, Berkeley, California 94720 and Department of Biochemistry & Biophysics, School of Medicine, University of California, San Francisco, California 94143

Correspondence: Address reprint requests to George Oster, Dept. of ESPM, University of California, 201 Wellman Hall, Berkeley, CA 94720-3112. Tel.: 510-642-5277; Fax: 510-642-7428; E-mail: goster{at}nature.berkeley.edu.

The difficulty in growing crystals for x-ray diffraction analysis has hindered the determination of membrane protein structures. However, this is changing with the advent of a new method for growing high quality membrane protein crystals from the lipidic cubic phase. Although successful, the mechanism underlying this method has remained unclear. Here, we present a theoretical analysis of the process. We show that it is energetically favorable for proteins embedded in the highly curved cubic phase to cluster together in flattened regions of the membrane. This stabilizes the lamellar phase, permitting its outgrowth from the cubic phase. A kinetic barrier-crossing model is developed to determine the free energy barrier to crystallization from the time-dependent growth of protein clusters. Determining the values of key parameters provides both a rational basis for optimizing the experimental procedure for membrane proteins that have not yet been crystallized and insight into the analogous cubic to lamellar transitions in cells. We also discuss the implications of this mechanism for protein sorting at the exit sites of the Golgi and endoplasmic reticulum and the general stabilization of membrane structures.

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