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Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott–Aldrich syndrome’ protein

Author

Listed:
  • Norzehan Abdul-Manan

    (Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center)

  • Behzad Aghazadeh

    (Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center
    Graduate Program in Physiology and Biophysics, Cornell University Graduate School of Medical Sciences)

  • Grace A. Liu

    (Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center)

  • Ananya Majumdar

    (Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center)

  • Ouathek Ouerfelli

    (Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center)

  • Katherine A. Siminovitch

    (Samuel Lunenfeld Research Institute, Mount Sinai Hospital)

  • Michael K. Rosen

    (Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center
    Graduate Program in Biochemstry and Structural Biology, Cornell University Graduate School of Medical Sciences)

Abstract

The Rho-family GTP-hydrolysing proteins (GTPases), Cdc42, Rac and Rho, act as molecular switches in signalling pathways that regulate cytoskeletal architecture, gene expression and progression of the cell cycle1. Cdc42 and Rac transmit many signals through GTP-dependent binding to effector proteins containing a Cdc42/Rac-interactive-binding (CRIB) motif2. One such effector, the Wiskott–Aldrich syndrome protein (WASP), is postulated to link activation of Cdc42 directly to the rearrangement of actin3. Human mutations in WASP cause severe defects in haematopoletic cell function, leading to clinical symptoms of thrombocytopenia, immunodeficiency and eczema. Here we report the solution structure of a complex between activated Cdc42 and a minimal GTPase-binding domain (GBD) from WASP. An extended amino-terminal GBD peptide that includes the CRIB motif contacts the switch I, β2 and α5 regions of Cdc42. A carboxy-terminal β-hairpin and α-helix pack against switch II. The Phe-X-His-X2-His portion of the CRIB motif and the α-helix appear to mediate sensitivity to the nucleotide switch through contacts to residues 36–40 of Cdc42. Discrimination between the Rho-family members is likely to be governed by GBD contacts to the switch I and α5 regions of the GTPases. Structural and biochemical data suggest that GBD-sequence divergence outside the CRIB motif may reflect additional regulatory interactions with functional domains that are specific to individual effectors.

Suggested Citation

  • Norzehan Abdul-Manan & Behzad Aghazadeh & Grace A. Liu & Ananya Majumdar & Ouathek Ouerfelli & Katherine A. Siminovitch & Michael K. Rosen, 1999. "Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott–Aldrich syndrome’ protein," Nature, Nature, vol. 399(6734), pages 379-383, May.
  • Handle: RePEc:nat:nature:v:399:y:1999:i:6734:d:10.1038_20726
    DOI: 10.1038/20726
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    1. Fabienne Kocher & Violetta Applegate & Jens Reiners & Astrid Port & Dominik Spona & Sebastian Hänsch & Amin Mirzaiebadizi & Mohammad Reza Ahmadian & Sander H. J. Smits & Johannes H. Hegemann & Katja M, 2024. "The Chlamydia pneumoniae effector SemD exploits its host’s endocytic machinery by structural and functional mimicry," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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