Optineurin 识别活性 Rab8a 的分子基础。

IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Biology Pub Date : 2024-10-05 DOI:10.1016/j.jmb.2024.168811
Jing Zhang , Lei Liu , Miao Li , Haobo Liu , Xinyu Gong , Yubin Tang , Yuchao Zhang , Xindi Zhou , Zhiqiao Lin , Hanbo Guo , Lifeng Pan
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引用次数: 0

摘要

光神经蛋白(OPTN)是哺乳动物体内的一种多功能适配蛋白,在许多细胞过程(如囊泡转运和自噬)中发挥着关键作用。值得注意的是,光神经蛋白的突变与许多人类疾病直接相关,如肌萎缩性脊髓侧索硬化症(ALS)。OPTN能特异性识别Rab8a和GTP酶激活蛋白TBC1D17,并促进由TBC1D17介导的Rab8a失活,但其机制尚不清楚。在这里,我们利用生化和结构方法系统地描述了 OPTN 与 Rab8a 之间的相互作用,发现 OPTN 通过其亮氨酸-拉链结构域(LZD)选择性地识别 GTP 结合的活性 Rab8a。确定的 OPTN LZD 与活性 Rab8a 复合物的晶体结构不仅阐明了 OPTN 与 Rab8a 结合的详细机制,还揭示了 Rab8a 与其效应物的独特结合模式。此外,我们还证明了 OPTN 和活性 Rab8a 的中央盘卷结构域可同时与 TBC1D17 的 TBC 结构域相互作用,形成三元复合物。最后,基于 OPTN LZD/Rab8a 复合物结构和相关生化分析,我们还评估了在 OPTN LZD 中发现的几种已知 ALS 相关突变。总之,我们的研究结果为 OPTN 与 Rab8a 的相互作用提供了机理上的见解,拓展了我们对 Rab8a 与其效应物的结合模式以及由 OPTN 突变引起的疾病的潜在病因的理解。
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Molecular Basis of the Recognition of the Active Rab8a by Optineurin
Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism. Here, using biochemical and structural approaches, we systematically characterize the interaction between OPTN and Rab8a, revealing that OPTN selectively recognizes the GTP-bound active Rab8a through its leucine-zipper domain (LZD). The determined crystal structure of OPTN LZD in complex with the active Rab8a not only elucidates the detailed binding mechanism of OPTN with Rab8a but also uncovers a unique binding mode of Rab8a with its effectors. Furthermore, we demonstrate that the central coiled-coil domain of OPTN and the active Rab8a can simultaneously interact with the TBC domain of TBC1D17 to form a ternary complex. Finally, based on the OPTN LZD/Rab8a complex structure and relevant biochemical analyses, we also evaluate several known ALS-associated mutations found in the LZD of OPTN. Collectively, our findings provide mechanistic insights into the interaction of OPTN with Rab8a, expanding our understanding of the binding modes of Rab8a with its effectors and the potential etiology of diseases caused by OPTN mutations.
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来源期刊
Journal of Molecular Biology
Journal of Molecular Biology 生物-生化与分子生物学
CiteScore
11.30
自引率
1.80%
发文量
412
审稿时长
28 days
期刊介绍: Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.
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