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首页> 外文期刊>Journal of Molecular Biology >Biophysical basis of the binding of WWOX tumor suppressor to WBP1 and WBP2 adaptors
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Biophysical basis of the binding of WWOX tumor suppressor to WBP1 and WBP2 adaptors

机译：WWOX抑癌剂与WBP1和WBP2衔接子结合的生物物理基础

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摘要

The WW-containing oxidoreductase (WWOX) tumor suppressor participates in a diverse array of cellular activities by virtue of its ability to recognize WW-binding protein 1 (WBP1) and WW-binding protein 2 (WBP2) signaling adaptors among a wide variety of other ligands. Herein, using a multitude of biophysical techniques, we provide evidence that while the WW1 domain of WWOX binds to PPXY motifs within WBP1 and WBP2 in a physiologically relevant manner, the WW2 domain exhibits no affinity toward any of these PPXY motifs. Importantly, our data suggest that while R25/W44 residues located within the binding pocket of a triple-stranded β-fold of WW1 domain are critical for the recognition of PPXY ligands, they are replaced by the chemically distinct E66/Y85 duo at structurally equivalent positions within the WW2 domain, thereby accounting for its failure to bind PPXY ligands. Predictably, not only does the introduction of E66R/Y85W double substitution within the WW2 domain result in gain of function but the resulting engineered domain, hereinafter referred to as WW2-RW, also appears to be a much stronger binding partner of WBP1 and WBP2 than the wild-type WW1 domain. We also show that while the WW1 domain is structurally disordered and folds upon ligand binding, the WW2 domain not only adopts a fully structured conformation but also aids stabilization and ligand binding to WW1 domain. This salient observation implies that the WW2 domain likely serves as a chaperone to augment the physiological function of WW1 domain within WWOX. Collectively, our study lays the groundwork for understanding the molecular basis of a key protein-protein interaction pertinent to human health and disease.
机译：含WW的氧化还原酶（WWOX）肿瘤抑制因子凭借其识别WW结合蛋白1（WBP1）和WW结合蛋白2（WBP2）信号转导子的能力参与多种细胞活动。配体。在这里，我们使用多种生物物理技术提供的证据表明，虽然WWOX的WW1结构域以生理相关的方式与WBP1和WBP2中的PPXY基序结合，但是WW2结构域对这些PPXY基序中的任何一个都没有亲和力。重要的是，我们的数据表明，虽然WW1结构域三链β折叠的结合口袋中的R25 / W44残基对于识别PPXY配体至关重要，但它们被化学上不同的E66 / Y85二重位取代，结构上等效在WW2结构域中的位置，从而解释了其不能结合PPXY配体的原因。可以预见，不仅在WW2结构域中引入E66R / Y85W双取代会导致功能获得，而且所得的工程化结构域（以下称为WW2-RW）似乎比WBP1和WBP2具有更强的结合伴侣野生型WW1域。我们还显示，虽然WW1域在结构上是无序的并且在配体结合后折叠，但WW2域不仅采用完全结构化的构象，而且还有助于稳定化和配体与WW1域结合。这一显着观察表明，WW2域可能充当伴侣，以增强WWOX中WW1域的生理功能。总体而言，我们的研究为理解与人类健康和疾病相关的关键蛋白质与蛋白质相互作用的分子基础奠定了基础。

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