The Wiskott-Aldrich Syndrome Protein (WASP; also called Bee1p) and its homolog N (neuronal)-WASP are signal transduction proteins that promote actin polymerization in response to upstream intracellular signals. WAS is an X-linked recessive disease, characterized by eczema, immunodeficiency, and thrombocytopenia. The majority of patients with WAS, or a milder version of the disorder, X-linked thrombocytopenia (XLT), have point mutations in the EVH1 domain of WASP. WASP is an actin regulatory protein consisting of an N-terminal EVH1 domain called WH1 which binds LPPPEP peptides, a basic region (B), a GTP binding domain (GBP), a proline rich region, a WH2 domain, and a verprolin-cofilin-acidic motif (VCA) which activates the actin-related protein (Arp)2/3 actin nucleating complex. The B, GBD, and the proline-rich region are involved in autoinhibitory interactions that repress or block the activity of the VCA. Yeast members lack the GTP binding domain. The EVH1 domains are part of the PH domain superamily. There are 5 EVH1 subfamilies: Enables/VASP, Homer/Vesl, WASP, Dcp1, and Spred. Ligands are known for three of the EVH1 subfamilies, all of which bind proline-rich sequences: the Enabled/VASP family binds to FPPPP peptides, the Homer/Vesl family binds PPxxF peptides, and the WASP family binds LPPPEP peptides. EVH1 has a PH-like fold, despite having minimal sequence similarity to PH or PTB domains.
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