Structure of the N-WASP EVH1 domain-WIP complex: Insight into the molecular basis of Wiskott-Aldrich Syndrome
Structure of the N-WASP EVH1 domain-WIP complex: Insight into the molecular basis of Wiskott-Aldrich Syndrome
复制标题
DOI：
10.1016/s0092-8674(02)01076-0
复制
发表时间：
2002-11-15
期刊：
影响因子：
64.5
通讯作者：
Lim, WA
中科院分区：
文献类型：
--
作者：
Volkman, BF;Prehoda, KE;Lim, WA
导致免疫疾病 Wiskott-Aldrich 综合征 (WAS) 的错义突变体主要定位于肌动蛋白调节蛋白 WASP 的 Enabled/VASP 同源 1 (EVH1) 结构域。该结构域与肽和磷脂的结合有关。我们在此表明，N-WASP EVH1 结构域不与先前报道的磷脂酰肌醇-(4,5)-二磷酸结合，但确实与 WASP 相互作用蛋白 (WIP) 的 25 个残基基序特异性结合。该复合物的核磁共振结构揭示了一种新的识别机制——WIP配体比典型的EVH1配体长得多，包裹着结构域，接触狭窄但延伸的表面。这种识别机制为理解导致 WAS 的突变的影响提供了基础。
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.