Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
Biomolecules. 2020 Jul 21;10(7):1084. doi: 10.3390/biom10071084.
WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein-protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP's protein-protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent.
WASp 相互作用蛋白（WIP）是细胞中肌动蛋白细胞骨架组装和重塑的调节剂，是一种多功能蛋白，也是蛋白质相互作用网络的关键成员，对健康和疾病有重要影响。在这里，我们试图从细胞生物学研究中对 WIP 功能的已有充分了解出发，通过对 WIP 相互作用的结构描述进行补充，重点介绍了呈现 WIP 蛋白质-蛋白质相互作用分子视角的工作，这提供了对 WIP 介导其生物学功能的机制的更深入理解。完全无序的 WIP 也是一个有趣的例子，说明了无规卷曲蛋白（IDP）如何发挥其功能。WIP 由连续的小功能域和基序组成，与许多细胞伴侣相互作用，其中富含脯氨酸的基序与几个公认的结合伴侣有很强的相互作用能力；事实上，WIP 一级结构的 30%以上是脯氨酸残基。我们专注于三个重要的 WIP 片段的结合基序和结合界面，即肌动蛋白结合的 N 端结构域、与各种相互作用伙伴的 SH3 结构域结合的中央结构域，以及与 WASp 结合的 C 端结构域。除了对这种核心细胞因子生物学有更深入的理解具有明显的重要性外，这种方法对针对 WIP 及其结合伙伴的药物设计工作也有直接的、非常有益的影响。这些因素使这些结构研究的价值变得显而易见，尽管它们具有挑战性。
