Rho family small GTPases are critical regulators of multiple cellular functions. Dbl-homology-domain-containing proteins are the classical GEFs (guanine nucleotide exchange factors) responsible for activation of Rho proteins. Zizimin1 is a Cdc42-specific GEF that belongs to a second family of mammalian Rho-GEFs, CZH [CDM (Ced-5/DOCK180/Myoblast city)-zizimin homology] proteins, which possess a novel type of GEF domain. CZH proteins can be divided into a subfamily related to DOCK 180 and a subfamily related to zizimin1. The two groups share two conserved regions named the CZH1 (or DHR1) domain and the CZH2 (DHR2 or DOCKER) domains, the latter exhibiting GEF activity. We now show that limited proteolysis of zizimin1 suggests the existence of structural domains that do not correspond to those identified on the basis of homologies. We demonstrate that the N-terminal half binds to the GEF domain through three distinct areas, including the CZH1, to inhibit the interaction with Cdc42. The N-terminal PH (pleckstrin homology) domain binds phosphoinositides and mediates zizimin1 membrane targeting. These results define two novel functions for the N-terminal region of zizimin1.
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Research Article|
December 21 2007
Function of the N-terminus of zizimin1: autoinhibition and membrane targeting
Nahum Meller;
Nahum Meller
*Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, U.S.A.
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M. Jody Westbrook;
M. Jody Westbrook
*Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, U.S.A.
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John D. Shannon;
John D. Shannon
†Department of Microbiology, University of Virginia, Charlottesville, VA 22908, U.S.A.
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Chittibabu Guda;
Chittibabu Guda
‡Gen*NY*sis Center for Excellence in Cancer Genomics, State University of New York at Albany, 1 Discovery Drive, Rensselaer, NY 12144, U.S.A.
§Department of Epidemiology and Biostatistics, State University of New York at Albany, 1 Discovery Drive, Rensselaer, NY 12144, U.S.A.
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Martin A. Schwartz
Martin A. Schwartz
1
*Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, U.S.A.
†Department of Microbiology, University of Virginia, Charlottesville, VA 22908, U.S.A.
∥Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, U.S.A.
¶Mellon Prostate Cancer Institute, University of Virginia, Charlottesville, VA 22908, U.S.A.
1To whom correspondence should be addressed (email maschwartz@virginia.edu).
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Publisher: Portland Press Ltd
Received:
September 13 2007
Revision Received:
October 09 2007
Accepted:
October 12 2007
Accepted Manuscript online:
October 12 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 409 (2): 525–533.
Article history
Received:
September 13 2007
Revision Received:
October 09 2007
Accepted:
October 12 2007
Accepted Manuscript online:
October 12 2007
Citation
Nahum Meller, M. Jody Westbrook, John D. Shannon, Chittibabu Guda, Martin A. Schwartz; Function of the N-terminus of zizimin1: autoinhibition and membrane targeting. Biochem J 15 January 2008; 409 (2): 525–533. doi: https://doi.org/10.1042/BJ20071263
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