Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins.
Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins.
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对神经退行性疾病相关 optineurin 和 TBK1 蛋白的相互作用和疾病机制的结构见解。
DOI：
10.1038/ncomms12708
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发表时间：
2016-09-13
影响因子：
16.6
通讯作者：
Pan, Lifeng
中科院分区：
文献类型：
--
作者：
Li, Faxiang;Xie, Xingqiao;Wang, Yingli;Liu, Jianping;Cheng, Xiaofang;Guo, Yujiao;Gong, Yukang;Hu, Shichen;Pan, Lifeng
optinineurin是一种重要的自噬受体，参与多种选择性自噬过程，其功能受TBK1调节。optinineurin和TBK1的突变都与神经退行性疾病有关。然而，optinurin和TBK1之间特定相互作用的机制基础仍然是难以捉摸的。在这里，我们确定了optinineurin /TBK1复合物和相关的NAP1/TBK1复合物的晶体结构，揭示了optinineurin和TBK1相互作用的详细分子机制，并揭示了TBK1与其相关接头蛋白之间的一般结合模式。此外，我们发现青光眼相关的optineurin E50K突变不仅增强了optineurin与TBK1之间的相互作用，还改变了optineurin的寡聚状态，而als相关的TBK1 E696K突变特异性地破坏了optineurin/TBK1复合物的形成，但对NAP1/TBK1复合物的影响很小。因此，我们的研究为目前已知的在患者中发现的致病的optinineurin和TBK1突变提供了机制见解。引起与TBK1相互作用缺陷的视神经蛋白突变与神经退行性疾病有关。在这里，作者报告了这种复合物的结构，并概述了这些蛋白质的一般结合模式。
Optineurin is an important autophagy receptor involved in several selective autophagy processes, during which its function is regulated by TBK1. Mutations of optineurin and TBK1 are both associated with neurodegenerative diseases. However, the mechanistic basis underlying the specific interaction between optineurin and TBK1 is still elusive. Here we determine the crystal structures of optineurin/TBK1 complex and the related NAP1/TBK1 complex, uncovering the detailed molecular mechanism governing the optineurin and TBK1 interaction, and revealing a general binding mode between TBK1 and its associated adaptor proteins. In addition, we demonstrate that the glaucoma-associated optineurin E50K mutation not only enhances the interaction between optineurin and TBK1 but also alters the oligomeric state of optineurin, and the ALS-related TBK1 E696K mutation specifically disrupts the optineurin/TBK1 complex formation but has little effect on the NAP1/TBK1 complex. Thus, our study provides mechanistic insights into those currently known disease-causing optineurin and TBK1 mutations found in patients. Mutations in optineurin that cause defects in the interaction with TBK1 are associated with neurodegenerative diseases. Here, the authors report the structure of this complex, and outline a general binding mode for these proteins.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.5
作者：
Chi ZL;Akahori M;Obazawa M;Minami M;Noda T;Nakaya N;Tomarev S;Kawase K;Yamamoto T;Noda S;Sasaoka M;Shimazaki A;Takada Y;Iwata T
通讯作者：
Iwata T
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
16
作者：
Heo JM;Ordureau A;Paulo JA;Rinehart J;Harper JW
通讯作者：
Harper JW