Structural basis for the ARF GAP activity and specificity of the C9orf72 complex.
Structural basis for the ARF GAP activity and specificity of the C9orf72 complex.
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DOI：
10.1038/s41467-021-24081-0
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发表时间：
2021-06-18
影响因子：
16.6
通讯作者：
Hurley JH
中科院分区：
文献类型：
--
作者：
Su MY;Fromm SA;Remis J;Toso DB;Hurley JH
C9 ORF 72突变是肌萎缩侧索硬化症（ALS）和额颞叶变性（FTD）最常见的遗传原因，这是由于功能的获得和丧失。C9 orf 72与SMCR 8和WDR 41形成复合物，据报道其对ARF蛋白、RAB 8A和RAB 11 A具有GT3活化蛋白活性。我们确定了与C9 orf 72：SMCR 8：WDR 41结合的ARF 1-GDP-BeF 3的冷冻电镜结构。SMCR 8longin和C9 orf 72 longin结构域形成ARF 1的结合口袋。C9 orf 72 longin结构域的一面将ARF 1固定在适当的位置，而SMR 8longin将催化指Arg 147定位在ARF 1活性位点。ARF 1和C9 orf 72的界面残基突变降低或消除GAP活性。RAB 8A GAP需要比ARF 1高约10倍的C9 orf 72复合物浓度。这些数据支持C9 orf 72复合物作为ARF GAP的特定功能。该结构还提供了FLCN和NPRL 2的长蛋白结构域GAP的活性形式的模型，所述长蛋白结构域GAP调节mTORC 1途径的Rag GTP酶。据报道，C9 orf 72：SMCR 8：WDR 41复合物对ARF家族蛋白和RAB蛋白RAB 8A和RAB 11 A都具有GAP活性。在这里，作者提供了C9 orf 72复合物作为ARF GAP的特定功能的结构和生物化学证据，以及含有长蛋白的GAP家族差距活性的结构框架。
Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF3- bound to C9orf72:SMCR8:WDR41. The SMCR8longin and C9orf72longin domains form the binding pocket for ARF1. One face of the C9orf72longin domain holds ARF1 in place, while the SMCR8longin positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP. The structure also provides a model for the active forms of the longin domain GAPs of FLCN and NPRL2 that regulate the Rag GTPases of the mTORC1 pathway. C9orf72:SMCR8:WDR41 complex has been reported to have GAP activity for both ARF family proteins and the RAB proteins RAB8A and RAB11A. Here the authors provide structural and biochemical evidence for a specific function of the C9orf72 complex as an ARF GAP, and a structural framework for the GAP activity of the longin-containing GAP family.
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