Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency caused by mutations in the N-terminal EVH1 domain of Wiskott-Aldrich syndrome protein (WASP), a central cytoskeletal regulator in hematopoietic cells. In homeostasis, a critical balance must be maintained between activation and degradation of WASP, and charged with this role is WASP-interacting protein (WIP), an actin-binding multitasker involved in numerous protein-protein interactions. While at rest, the WIP C-terminal chaperone domain shields WASP from degradation; its phosphorylation-mediated dissociation leads to activation of the complex and initiation of the actin polymerization cascade. Using biomolecular NMR, we have determined the WASP/WIP structure and provided unprecedented molecular insight into how the WIP chaperone function is fine-tuned by phosphorylation and dysregulated with pathological consequences by WAS-inducing mutations. The central feature of this complex is the extensive binding interface formed by four WIP epitopes (epi I -epi IV ) that wrap around the canonical EVH1 binding surface. Phosphoregulation of the WIP chaperone function occurs on two tyrosines in epi III and epi IV , and not a distal serine residue as suggested earlier, and the ensuing partial dissociation of epi IV exposes two established WASP ubiquitylation sites. Single-residue WAS-inducing mutations with mild clinical phenotypes (sometimes manifested as X-linked thrombocytopenia, XLT) influence the same WASP-epi IV interface, consistent with low WASP levels observed in such patients. In contrast, mutations interfering with the WASP-epi I /epi II interface which “anchors” the chaperone on the WASP surface cause severe phenotypes due to overall loss of WASP stability. This structural viewpoint of WASP/WIP biology creates a much-needed molecular context for understanding hematopoietic cytoskeletal regulation and is expected to be invaluable in the search for long-sought new therapeutic approaches to these rare diseases.
Sasson et al. (2026) studied this question.