Einbond A, Sudol M
Department of Biochemistry, Mount Sinai School of Medicine, New York, NY 10029-6547, USA.
FEBS Lett. 1996 Apr 8;384(1):1-8. doi: 10.1016/0014-5793(96)00263-3.
The WW domain is a structured protein module found in a wide range of regulatory, cytoskeletal, and signaling molecules. Its ligands contain proline-rich sequences, some of which show a core consensus of XPPXY that is critical for binding. In order to gain a better understanding of the molecular and biological functions of WW domains, we decided to predict their cognate ligands by searching databases for proteins containing the XPPXY consensus. Using several axioms that take into account evolutionary conservation and functional similarity, we have identified four groups of proteins representing candidate ligands that signal through known or unknown WW domains. These include viral Gag proteins, sodium channels, interleukin receptors, and a subgroup of serine/threonine kinases. In addition, we proposed that dystrophin and beta-dystroglycan bind through the WW-XPPXY link and that interference with this interaction could result in muscular dystrophy. Our study provides guidelines for experiments to probe the molecular and biological functions of the WW domain-ligand connection. Should these predictions be proven empirically, the results may have important ramifications for basic research and medicine.
WW 结构域是一种存在于多种调节、细胞骨架和信号分子中的结构化蛋白质模块。其配体含有富含脯氨酸的序列，其中一些显示出对结合至关重要的 XPPXY 核心共有序列。为了更好地理解 WW 结构域的分子和生物学功能，我们决定通过在数据库中搜索含有 XPPXY 共有序列的蛋白质来预测其同源配体。利用考虑进化保守性和功能相似性的几个公理，我们确定了四组蛋白质，它们代表通过已知或未知 WW 结构域发出信号的候选配体。这些包括病毒 Gag 蛋白、钠通道、白细胞介素受体和一组丝氨酸/苏氨酸激酶。此外，我们提出肌营养不良蛋白和β - 肌营养不良聚糖通过 WW - XPPXY 连接结合，并且干扰这种相互作用可能导致肌肉萎缩症。我们的研究为探索 WW 结构域 - 配体连接的分子和生物学功能的实验提供了指导。如果这些预测得到实证验证，结果可能对基础研究和医学产生重要影响。
