An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2
An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2
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DOI：
10.1074/jbc.m601493200
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发表时间：
2006-06-23
影响因子：
4.8
通讯作者：
Forman-Kay, Julie D.
中科院分区：
文献类型：
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作者：
Chong, P. Andrew;Lin, Hong;Forman-Kay, Julie D.
Smurf2是一种E3泛素连接酶，可驱动转化生长因子-β受体及其他靶标的降解。Smurf2对受体的识别是通过一种中介蛋白Smad7实现的。在此我们已经证明，Smurf2的WW3结构域能够直接与Smad7的多聚脯氨酸 - 酪氨酸（PY）基序结合。特别值得关注的是，与靶标PY基序相互作用的高度保守的WW结构域结合位点色氨酸，在Smurf2的WW3结构域中是苯丙氨酸。为了研究这种相互作用，我们确定了Smad7的PY基序区域（ELESPPPPYSRYPMD）与Smurf2的WW3结构域之间复合物的溶液结构。该结构显示，除了结合PY基序外，WW3结构域还结合PY基序C末端的6个残基（PY - 尾）。尽管WW3结构域结合位点中的苯丙氨酸相对于典型的色氨酸降低了亲和力，但这通过PY - 尾与WW3结构域的β1链以及β1 - β2环之间的额外相互作用得到了平衡。Smurf2的WW3结构域与Smad7的PY基序之间的相互作用是WW结构域中结合位点色氨酸被苯丙氨酸取代后识别PY基序的首个实例。这种不寻常的相互作用使得Smurf2的WW3结构域能够利用一个扩展的表面识别一部分含PY基序的蛋白质，从而提供特异性。
Smurf2 is an E3 ubiquitin ligase that drives degradation of the transforming growth factor-beta receptors and other targets. Recognition of the receptors by Smurf2 is accomplished through an intermediary protein, Smad7. Here we have demonstrated that the WW3 domain of Smurf2 can directly bind to the Smad7 polyproline-tyrosine (PY) motif. Of particular interest, the highly conserved WW domain binding site Trp, which interacts with target PY motifs, is a Phe in the Smurf2 WW3 domain. To examine this interaction, the solution structure of the complex between the Smad7 PY motif region (ELESPPPPYSRYPMD) and the Smurf2 WW3 domain was determined. The structure reveals that, in addition to binding the PY motif, the WW3 domain binds six residues C-terminal to the PY motif (PY-tail). Although the Phe in the WW3 domain binding site decreases affinity relative to the canonical Trp, this is balanced by additional interactions between the PY-tail and the beta 1-strand and beta 1-beta 2 loop of the WW3 domain. The interaction between the Smurf2 WW3 domain and the Smad7 PY motif is the first example of PY motif recognition by a WW domain with a Phe substituted for the binding site Trp. This unusual interaction allows the Smurf2 WW3 domain to recognize a subset of PY motif-containing proteins utilizing an expanded surface to provide specificity.