The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain.

The Journal of Biological Chemistry
Nahum MellerMartin A Schwartz

Abstract

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 approximately 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.

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Citations

Feb 20, 2010·The Journal of Biological Chemistry·Lakshmanane PremkumarRobert C Liddington
May 29, 2008·Journal of Cell Science·Julia MellerMartin Alexander Schwartz
May 24, 2008·Molecular Immunology·Estefanía YeloAntonio Parrado
Sep 4, 2007·Trends in Cell Biology·Jean-François Côté, Kristiina Vuori
Jan 22, 2009·Journal of Neuroscience Research·Kazuya KuramotoHironori Katoh
Aug 30, 2008·Journal of Cellular Biochemistry·Kimberly A BrownHarold L Moses
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