Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation
Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation
复制标题
OPTN (optineurin) 识别泛素及其受 TBK1 介导的磷酸化调节的结构见解。
DOI：
10.1080/15548627.2017.1391970
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Pan, Lifeng
中科院分区：
文献类型：
--
作者：
Li, Faxiang;Xu, Daichao;Pan, Lifeng
OPTN （optinurin）是一种泛素结合支架蛋白，在选择性自噬过程中是一种重要的巨噬/自噬受体。OPTN突变与包括ALS和青光眼在内的人类神经退行性疾病有关。然而，OPTN识别泛素及其通过tbk1介导的磷酸化调控的机制基础尚不清楚。在这里，我们证明OPTN的urban结构域优先识别线性泛素链，并与线性二泛素形成不对称的2:1化学配比复合物。此外，我们的研究结果为UBAN磷酸化如何调节OPTN的泛素结合能力以及OPTN城市结构域的疾病相关突变如何破坏其与泛素的相互作用提供了新的机制见解。最后，我们发现泛素结合缺陷可能影响OPTN向线性泛素修饰突变亨廷顿蛋白聚集体的募集。综上所述，我们的研究结果阐明了UBAN与线性泛素链之间的相互作用模式，并扩展了我们对OPTN识别泛素修饰底物的分子机制以及OPTN突变引起的神经退行性疾病的发病机制的认识。
OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an asymmetric 2:1 stoichiometry complex with the linear diubiquitin. In addition, our results provide new mechanistic insights into how phosphorylation of UBAN would regulate the ubiquitin-binding ability of OPTN and how disease-associated mutations in the OPTN UBAN domain disrupt its interaction with ubiquitin. Finally, we show that defects in ubiquitin-binding may affect the recruitment of OPTN to linear ubiquitin-decorated mutant Huntington protein aggregates. Taken together, our findings clarify the interaction mode between UBAN and linear ubiquitin chain in general, and expand our knowledge of the molecular mechanism of ubiquitin-decorated substrates recognition by OPTN as well as the pathogenesis of neurodegenerative diseases caused by OPTN mutations.