title: Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome.
abstract: Missense mutants that cause the immune disorder Wiskott-Aldrich Syndrome (WAS) map primarily to the Enabled/VASP homology 1 (EVH1) domain of the actin regulatory protein WASP. This domain has been implicated in both peptide and phospholipid binding. We show here that the N-WASP EVH1 domain does not bind phosphatidyl inositol-(4,5)-bisphosphate, as previously reported, but does specifically bind a 25 residue motif from the WASP Interacting Protein (WIP). The NMR structure of the complex reveals a novel recognition mechanism-the WIP ligand, which is far longer than canonical EVH1 ligands, wraps around the domain, contacting a narrow but extended surface. This recognition mechanism provides a basis for understanding the effects of mutations that cause WAS.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Prehoda
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Scott
authors.forename: Francis C
authors.initials: FC
authors.lastname: Peterson
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D003598:Cytoskeletal Proteins; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism; D011392:Proline; D017434:Protein Structure, Tertiary; D051381:Rats; D014923:Wiskott-Aldrich Syndrome; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D010455:Peptides; D019269:Phosphatidylinositol 4,5-Diphosphate; C495770:Wasl protein, rat; C491670:Wipf1 protein, rat; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D011392:Proline