Kato Yusuke, Miyakawa Takuya, Kurita Jun-Ichi, Tanokura Masaru
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
J Biol Chem. 2006 Dec 29;281(52):40321-9. doi: 10.1074/jbc.M609321200. Epub 2006 Oct 24.
FBP11/HYPA is a mammalian homologue of yeast splicing factor Prp40. The first WW domain of FBP11/HYPA (FBP11 WW1) is essential for preventing severe neurological diseases such as Huntington disease and Rett syndrome and strongly resembles the WW domain of FCA, the essential regulator for flowering time control. We have solved the structure of FBP11 WW1 and a Pro-Pro-Leu-Pro ligand complex, and demonstrated the binding mechanism with mutational analysis using surface plasmon resonance. The overall structure of FBP11 WW1 in the complex form is quite similar to the structures of WW domains from Group I and IV in complexes. In addition, conformation of FBP11 WW1 does not change much upon ligand binding. The binding orientation of the ligand against FBP11 WW1 is the same as that of the Group IV WW domain-ligand complex, but opposite to that of the Group I complex. The ligand interacts with two grooves formed by surface aromatic residues. The Pro and Leu residues in the ligand interact with the grooves and the Loop I region of FBP11 WW1, respectively, which are necessary interactions for binding the ligand. Interestingly, the two aromatic grooves recognize the Pro residues in entirely different manners, which allows FBP11 WW1 to recognize shorter sequences than the SH3 domain. Combined with homology models of other WW domains, the present report shows the detailed mechanism of ligand binding by Group II/III WW domains, and provides information useful in designing drugs to treat neurodegenerative diseases.
FBP11/HYPA是酵母剪接因子Prp40的哺乳动物同源物。FBP11/HYPA的第一个WW结构域（FBP11 WW1）对于预防诸如亨廷顿舞蹈症和雷特综合征等严重神经疾病至关重要，并且与FCA的WW结构域极为相似，FCA是控制开花时间的关键调节因子。我们解析了FBP11 WW1与一个脯氨酸-脯氨酸-亮氨酸-脯氨酸配体复合物的结构，并通过表面等离子体共振突变分析证明了其结合机制。复合物形式的FBP11 WW1的整体结构与复合物中第I组和第IV组WW结构域的结构非常相似。此外，FBP11 WW1的构象在配体结合时变化不大。配体与FBP11 WW1的结合方向与第IV组WW结构域-配体复合物相同，但与第I组复合物相反。配体与由表面芳香族残基形成的两个凹槽相互作用。配体中的脯氨酸和亮氨酸残基分别与FBP11 WW1的凹槽和环I区域相互作用，这是结合配体所必需的相互作用。有趣的是，这两个芳香族凹槽以完全不同的方式识别脯氨酸残基，这使得FBP11 WW1能够识别比SH3结构域更短的序列。结合其他WW结构域的同源模型，本报告展示了第II/III组WW结构域配体结合的详细机制，并提供了有助于设计治疗神经退行性疾病药物的有用信息。
