Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua
Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua
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DOI：
10.1101/gad.212068.112
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发表时间：
2013-03-15
影响因子：
10.5
通讯作者：
Song, Ji-Joon
中科院分区：
文献类型：
--
作者：
Kim, Eunji;Lu, Hsiang-Chih;Song, Ji-Joon
脊髓小脑性共济失调1型（SCA 1）是一种由Ataxin-1（ATXN 1）中多聚谷氨酰胺扩增引起的显性遗传性神经退行性疾病。ATXN 1与转录抑制因子Capicua（CIC）结合，这种相互作用在SCA 1发病机制中起着关键作用，从而降低CIC水平可以挽救小鼠模型中的SCA 1样表型。ATXN 1的ATXN 1/HBP 1（AXH）结构域介导其同源二聚化以及与CIC的相互作用。在这里，我们提出了ATXN 1的AXH域绑定到CIC的晶体结构，并显示AXH域CIC的结合口袋与AXH域的同源二聚口袋重叠。因此，与CIC的结合破坏了ATXN 1的同源二聚化。此外，CIC的结合重新配置复合物，以允许由CIC介导的另一种形式的二聚化，显示了ATXN 1和CIC的蛋白质复合物形成和重新配置的复杂性。鉴定介导CIC和ATXN 1之间相互作用的表面揭示了CIC在AXH二聚体重构中的关键作用，并可能提供深入了解靶向ATXN 1/CIC相互作用以调节SCA 1发病机制的方法。
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by polyglutamine expansion in Ataxin-1 (ATXN1). ATXN1 binds to the transcriptional repressor Capicua (CIC), and the interaction plays a critical role in SCA1 pathogenesis whereby reducing CIC levels rescues SCA1-like phenotypes in a mouse model. The ATXN1/HBP1 (AXH) domain of ATXN1 mediates its homodimerization as well as the interaction with CIC. Here, we present the crystal structure of ATXN1's AXH domain bound to CIC and show that the binding pocket of the AXH domain to CIC overlaps with the homodimerization pocket of the AXH domain. Thus, the binding to CIC disrupts the homodimerization of ATXN1. Furthermore, the binding of CIC reconfigures the complex to allow another form of dimerization mediated by CIC, showing the intricacy of protein complex formation and reconfiguration by ATXN1 and CIC. Identifying the surfaces mediating the interactions between CIC and ATXN1 reveals a critical role for CIC in the reconfiguration of the AXH dimers and might provide insight into ways to target the ATXN1/CIC interactions to modulate SCA1 pathogenesis.