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J. Biol. Chem., Vol. 283, Issue 26, 18377-18384, June 27, 2008

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A Structural Model of the GDP Dissociation Inhibitor Rab Membrane Extraction Mechanism^*

Alexander Ignatev¹, Sergey Kravchenko¹, Alexey Rak, Roger S. Goody, and Olena Pylypenko²

From the Max-Planck Institute for Molecular Physiology Dortmund Otto-Hahn-Strasse 11, 44227 Dortmund, Germany and the Institute of Physiological Chemistry, Ruhr University Bochum, 44780 Bochum, Germany

Rab GDP dissociation inhibitors (GDI)-facilitated extraction of prenylated Rab proteins from membranes plays an important role in vesicular membrane trafficking. The investigated thermodynamic properties of yeast Rab·GDI and Rab·MRS6 complexes demonstrated differences in the Rab binding properties of the closely related Rab GDI and MRS6 proteins, consistent with their functional diversity. The importance of the Rab C terminus and its prenylation for GDI/MRS6 binding was demonstrated using both biochemical and structural data. The presented structures of the apo-form yeast Rab GDI and its two complexes with unprenylated Rab proteins, together with the earlier published structures of the prenylated Ypt1·GDI, provide evidence of allosteric regulation of the GDI lipid binding site opening, which plays a key role in the proposed mechanism of GDI-mediated Rab extraction. We suggest a model for the interaction of GDI with prenylated Rab proteins that incorporates a stepwise increase in affinity as the three different partial interactions are successively formed.

Received for publication, November 28, 2007 , and in revised form, April 16, 2008.

The atomic coordinates and structure factors (code 3cpj, 3cph, and 3cpi) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work, conducted as part of the award made under the European Heads of Research Councils and European Science Foundation EURYI (European Young Investigator) Awards scheme in 2004 (to A. R.), was supported by funds from the Participating Organizations of EURYI, Deutsche Forschungsgemeinschaft Grant RA 1364/1-1, and the European Community Sixth Framework Programme. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49-231-1332304; Fax: 49-231-1332398; E-mail: pylypenk{at}mpi-dortmund.mpg.de.

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