WW domains provide a platform for the assembly of multiprotein networks
WW domains provide a platform for the assembly of multiprotein networks
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DOI：
10.1128/mcb.25.16.7092-7106.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Pawson, T
中科院分区：
文献类型：
--
作者：
Ingham, RJ;Colwill, K;Pawson, T
WW结构域是通过识别富含脯氨酸的肽基序和磷酸化丝氨酸/苏氨酸-脯氨酸位点介导蛋白质-蛋白质相互作用的蛋白质模块。为了研究WW结构域的功能特性，我们采用质谱法鉴定了与10个人类WW结构域相关的148个蛋白质。这些蛋白质中的许多代表了新的WW结构域结合伙伴，并且是参与分子过程（如转录、RNA加工和细胞骨架调节）的多蛋白复合物的组分。我们详细验证了一种复合物，表明AIP 4 E3蛋白-泛素连接酶的WW结构域以促进p68泛素化的方式直接与前mRNA切割和多聚腺苷酸化因子Im的p68亚基中的PPXY基序结合。测试的WW结构域分为三个大组的基础上的层次聚类相对于其相关的蛋白质，每个这样的集群的结合蛋白质显示了一组独特的WW结构域结合基序。我们还发现，来自相同蛋白质或密切相关蛋白质的单独的WW结构域可以对蛋白质配体具有不同的特异性，并且还证明了单个多肽可以通过单独的富含脯氨酸的基序结合多种类型的WW结构域。这些数据表明，WW结构域提供了一个通用的平台，将单个蛋白质连接到生理上重要的网络中。
WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs and phosphorylated serine/threonine-proline sites. To pursue the functional properties of WW domains, we employed mass spectrometry to identify 148 proteins that associate with 10 human WW domains. Many of these proteins represent novel WW domain-binding partners and are components of multiprotein complexes involved in molecular processes, such as transcription, RNA processing, and cytoskeletal regulation. We validated one complex in detail, showing that WW domains of the AIP4 E3 protein-ubiquitin ligase bind directly to a PPXY motif in the p68 subunit of pre-mRNA cleavage and polyadenylation factor Im in a manner that promotes p68 ubiquitylation. The tested WW domains fall into three broad groups on the basis of hierarchical clustering with respect to their associated proteins; each such cluster of bound proteins displayed a distinct set of WW domain-binding motifs. We also found that separate WW domains from the same protein or closely related proteins can have different specificities for protein ligands and also demonstrated that a single polypeptide can bind multiple classes of WW domains through separate proline-rich motifs. These data suggest that WW domains provide a versatile platform to link individual proteins into physiologically important networks.