Wiskott-Aldrich syndrome protein induces actin clustering without direct binding to Cdc42

WASP (Wiskott-Aldrich syndrome protein) was identified as the gene product whose mutation causes the human hereditary disease Wiskott-Aldrich syndrome . WASP contains many functional domains and has been shown to induce the fo rmation of clusters of actin filaments in a manner dependent on Cdc42. Howe ver, there has been no report investigating what domain(s) is(are) importan t for the function. Here we present for the first time the results of detai led analyses on the domain-function relationship of WASP. First, the C-term inal ver-prolin-cofilin-acidic domain was shown to be essential for the reg ulation of actin cytoskeleton. In addition, we found that the clustering of WASP itself is distinct from actin clustering, The partial protein contain ing the region from the N-terminal pleckstrin homology domain to the basic residue-rich region also clustered especially around the nucleus as wild ty pe WASP without inducing actin clustering. Finally, we obtained the quite u nexpected result that; a WASP mutant deficient in binding to Cdc42 still in duced actin cluster formation, indicating that direct interaction between C dc42 and WASP is not required for the regulation of actin cytoskeleton. Thi s result may explain why no Wiskott-Aldrich syndrome patients have been ide ntified with a missense mutation in the Cdc42-binding site.