Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly.

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  • Author(s): Chereau D;Chereau D; Kerff F; Graceffa P; Grabarek Z; Langsetmo K; Dominguez R
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2005 Nov 15; Vol. 102 (46), pp. 16644-9. Date of Electronic Publication: 2005 Nov 07.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Actins/*metabolism ; Wiskott-Aldrich Syndrome Protein/*chemistry; Amino Acid Sequence ; Calorimetry ; Models, Molecular ; Molecular Sequence Data ; Nucleotides/metabolism ; Protein Binding ; Sequence Homology, Amino Acid ; Structure-Activity Relationship ; Wiskott-Aldrich Syndrome Protein/metabolism
    • Abstract:
      Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) is a small and widespread actin-binding motif. In the WASP family, WH2 plays a role in filament nucleation by Arp2/3 complex. Here we describe the crystal structures of complexes of actin with the WH2 domains of WASP, WASP-family verprolin homologous protein, and WASP-interacting protein. Despite low sequence identity, WH2 shares structural similarity with the N-terminal portion of the actin monomer-sequestering thymosin beta domain (Tbeta). We show that both domains inhibit nucleotide exchange by targeting the cleft between actin subdomains 1 and 3, a common binding site for many unrelated actin-binding proteins. Importantly, WH2 is significantly shorter than Tbeta but binds actin with approximately 10-fold higher affinity. WH2 lacks a C-terminal extension that in Tbeta4 becomes involved in monomer sequestration by interfering with intersubunit contacts in F-actin. Owing to their shorter length, WH2 domains connected in tandem by short linkers can coexist with intersubunit contacts in F-actin and are proposed to function in filament nucleation by lining up actin subunits along a filament strand. The WH2-central region of WASP-family proteins is proposed to function in an analogous way by forming a special class of tandem repeats whose function is to line up actin and Arp2 during Arp2/3 nucleation. The structures also suggest a mechanism for how profilin-binding Pro-rich sequences positioned N-terminal to WH2 could feed actin monomers directly to WH2, thereby playing a role in filament elongation.
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    • Grant Information:
      R01 GM073791 United States GM NIGMS NIH HHS; GM073791 United States GM NIGMS NIH HHS
    • Molecular Sequence:
      PDB 2A3Z; 2A40; 2A41; 2A42
    • Accession Number:
      0 (Actins)
      0 (Nucleotides)
      0 (WAS protein, human)
      0 (Wiskott-Aldrich Syndrome Protein)
    • Publication Date:
      Date Created: 20051109 Date Completed: 20060203 Latest Revision: 20181113
    • Publication Date:
      20221213
    • Accession Number:
      PMC1283820
    • Accession Number:
      10.1073/pnas.0507021102
    • Accession Number:
      16275905