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Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein

Author

Listed:
  • Annette S. Kim

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

  • Lazaros T. Kakalis

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

  • Norzehan Abdul-Manan

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

  • Grace A. Liu

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

  • Michael K. Rosen

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

Abstract

The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott–Aldrich syndrome protein (WASP) family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins. Here we report the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex. Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery. These data show that ‘intrinsically unstructured’ peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context.

Suggested Citation

  • Annette S. Kim & Lazaros T. Kakalis & Norzehan Abdul-Manan & Grace A. Liu & Michael K. Rosen, 2000. "Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein," Nature, Nature, vol. 404(6774), pages 151-158, March.
    • Handle: RePEc:nat:nature:v:404:y:2000:i:6774:d:10.1038_35004513
    DOI: 10.1038/35004513
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    Cited by:

    1. Bojian Ding & Sheng Yang & Matthias Schaks & Yijun Liu & Abbigale J. Brown & Klemens Rottner & Saikat Chowdhury & Baoyu Chen, 2022. "Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Norbert S. Hill & Matthew D. Welch, 2022. "A glycine-rich PE_PGRS protein governs mycobacterial actin-based motility," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. 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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