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Molecular basis for Rac1 recognition by guanine nucleotide exchange factors

Nature Structural Biology volume 8, pages 1037–1041 (2001)Cite this article

Abstract

Rho GTPases are activated by a family of guanine nucleotide exchange factors (GEFs) known as Dbl family proteins. The structural basis for how GEFs recognize and activate Rho GTPases is presently ill defined. Here, we utilized the crystal structure of the DH/PH domains of the Rac-specific GEF Tiam1 in complex with Rac1 to determine the structural elements of Rac1 that regulate the specificity of this interaction. We show that residues in the Rac1 β2–β3 region are critical for Tiam1 recognition. Additionally, we determined that a single Rac1-to-Cdc42 mutation (W56F) was sufficient to abolish Rac1 sensitivity to Tiam1 and allow recognition by the Cdc42-specific DH/PH domains of Intersectin while not impairing Rac1 downstream activities. Our findings identified unique GEF specificity determinants in Rac1 and provide important insights into the mechanism of DH/PH selection of GTPase targets.

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Figure 1: Residues in the Rac1 β2–β3 region involved in specific recognition of the Tiam1 DH domain.
Figure 2: Consequences of mutations in Rac1 β2–β3 region on stimulation by the Tiam1 and Intersectin DH/PH domains.
Figure 3: Consequences of the W56F mutation on Rac1(61L) signaling and transformation.
Figure 4: Consequences of the W56F mutation on Rac1-induced membrane ruffling.

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Acknowledgements

We thank M. Pham for Tiam1 and Intersectin DH/PH protein preparations, Q. Lambert and H. Mehta for cell culture preparations and M. Rand for figure preparation. This work was supported by NIH grants to C.J.D. and S.L.C. D.K.W. is supported by a grant from the American Cancer Society. J.S. acknowledges the support from the NIH and the Pew Charitable Trusts.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, 27599, North Carolina, USA

    Antoine E. Karnoub, Kent L. Rossman, Sharon L. Campbell & John Sondek

  2. Department of Pharmacology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, 27599, North Carolina, USA

    Antoine E. Karnoub, David K. Worthylake, Wendy Morse Pruitt, John Sondek & Channing J. Der

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  1. Antoine E. Karnoub
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Correspondence to Channing J. Der.

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Karnoub, A., Worthylake, D., Rossman, K. et al. Molecular basis for Rac1 recognition by guanine nucleotide exchange factors. Nat Struct Mol Biol 8, 1037–1041 (2001). https://doi.org/10.1038/nsb719

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