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J. Biol. Chem., Vol. 279, Issue 36, 37470-37476, September 3, 2004

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The Novel Cdc42 Guanine Nucleotide Exchange Factor, Zizimin1, Dimerizes via the Cdc42-binding CZH2 Domain^*

Nahum Meller, Mohammad Irani-Tehrani, Boris I. Ratnikov, Bryce M. Paschal¶||, and Martin Alexander Schwartz**¶¶

From the Cardiovascular Research Center and Departments of ^**Microbiology, Biomedical Engineering, and ^¶Pharmacology, Mellon Prostate Cancer Institute, and the ^||Center of Cell Signaling, University of Virginia, Charlottesville, Virginia 22908 and the Department of Cell Biology, Scripps Research Institute, La Jolla, California 92037

Rho family small GTPases are critical regulators of multiple cellular processes and activities. Dbl homology domain-containing proteins are the classical guanine nucleotide exchange factors (GEFs) responsible for activation of Rho proteins. Recently another group of mammalian Rho-GEFs was discovered that includes CDM (Ced-5, DOCK180, Myoblast city) proteins that activate Rac and zizimin1 that activates Cdc42 via a nonconventional GEF module that we named the CZH2 domain. We report here that zizimin1 dimerizes via the CZH2 domain and that dimers are the only form detected. Dimerization was mapped to a 200-amino acid region that overlaps but is distinct from the Cdc42-binding sequences. Rotary shadowing electron microscopy revealed zizimin1 to be a symmetric, V-shaped molecule. Experiments with DOCK180 and homology analysis suggest that dimerization may be a general feature of CZH proteins. Deletion and mutation analysis indicated existence of individual Cdc42-binding sites in the zizimin1 monomers. Kinetic measurements demonstrated increased binding affinity of Cdc42 to zizimin1 at higher Cdc42 concentration, suggesting positive cooperativity. These features are likely to be critical for Cdc42 activation.

Received for publication, April 23, 2004 , and in revised form, July 1, 2004.

^* 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.

^¶¶ To whom correspondence should be addressed. E-mail: maschwartz{at}virginia.edu.

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