Article (Scientific journals)
Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly.
Chereau, David; Kerff, Frédéric; Graceffa, Philip et al.
2005In Proceedings of the National Academy of Sciences of the United States of America, 102 (46), p. 16644-9
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Keywords :
Actins/metabolism; Amino Acid Sequence; Calorimetry; Models, Molecular; Molecular Sequence Data; Nucleotides/metabolism; Protein Binding; Sequence Homology, Amino Acid; Structure-Activity Relationship; Wiskott-Aldrich Syndrome Protein/chemistry/metabolism
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Chereau, David
Kerff, Frédéric  ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Graceffa, Philip
Grabarek, Zenon
Langsetmo, Knut
Dominguez, Roberto
Language :
English
Title :
Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly.
Publication date :
2005
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
0027-8424
eISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington, United States - District of Columbia
Volume :
102
Issue :
46
Pages :
16644-9
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 12 February 2010

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