Structural basis of Tom20 and Tom22 cytosolic domains as the human TOM complex receptors.
Structural basis of Tom20 and Tom22 cytosolic domains as the human TOM complex receptors.
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Tom20 和 Tom22 胞质结构域作为人类 TOM 复合物受体的结构基础
DOI：
10.1073/pnas.2200158119
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发表时间：
2022-06-28
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
TOM复合物在胞质溶胶中合成的蛋白质转运到线粒体中中起核心作用。Tom 20、Tom 22和Tom 70作为TOM复合物的受体成分，在这一过程中起着关键作用。然而，Tom 20和Tom 22如何作为受体发挥作用尚不完全清楚。在这里，使用冷冻电子显微镜，我们捕获了TOM复合物的结构与可见的胞质结构域的Tom 20和Tom 22。我们发现，Tom 22有一个类似的三螺旋束结构在其N-末端胞质结构域的C-末端胞质结构域的Tom 20。此外，生物化学实验表明Tom 22的这种结构负责与前序列结合。这些结果为理解线粒体受体介导的转运过程提供了重要信息。线粒体前体蛋白在细胞质中合成，通过外膜多亚基转位酶（TOM）复合体输入线粒体。TOM复合物的组分Tom 20、Tom 22和Tom 70作为受体发挥功能，识别前序列并进一步引导蛋白质易位。它们的缺乏与神经退行性疾病和心脏病理学有关。尽管低温电子显微镜（cryo-EM）已经报道了TOM复合物的几种结构，但Tom 22和Tom 20如何作为TOM受体发挥作用仍然是难以捉摸的。在此，我们确定了2.53 nm处TOM核心复合物的结构，并在3.74 nm处捕获了含有Tom 22和Tom 20胞质结构域的TOM复合物的结构。结构分析表明Tom 20和Tom 22在胞质结构域中具有相似的三螺旋束结构特征。进一步的结构指导的生化分析表明，Tom 22胞质结构域是负责结合的前序列，螺旋H1是这种结合的关键。总之，我们的研究结果提供了深入了解的功能机制的TOM复合物识别和转移前蛋白跨越线粒体膜。
The TOM complex plays a central role in translocation of proteins synthesized in cytosol into the mitochondria. As the receptor components of the TOM complex, Tom20, Tom22, and Tom70 play pivotal roles in this process. How Tom20 and Tom22 function as receptors, however, is not fully understood. Here, using cryoelectron microscopy, we captured the structure of the TOM complex with visible cytosolic domain of Tom20 and Tom22. We show that Tom22 has a similar three-helix bundle structure at its N-terminal cytosolic domain to the C-terminal cytosolic domain of Tom20. Furthermore, the biochemical experiments demonstrated that this structure of Tom22 is responsible for binding with presequence. These results provide important information for understanding the receptor-guided transport process of mitochondria. Mitochondrial preproteins synthesized in cytosol are imported into mitochondria by a multisubunit translocase of the outer membrane (TOM) complex. Functioned as the receptor, the TOM complex components, Tom 20, Tom22, and Tom70, recognize the presequence and further guide the protein translocation. Their deficiency has been linked with neurodegenerative diseases and cardiac pathology. Although several structures of the TOM complex have been reported by cryoelectron microscopy (cryo-EM), how Tom22 and Tom20 function as TOM receptors remains elusive. Here we determined the structure of TOM core complex at 2.53 Å and captured the structure of the TOM complex containing Tom22 and Tom20 cytosolic domains at 3.74 Å. Structural analysis indicates that Tom20 and Tom22 share a similar three-helix bundle structural feature in the cytosolic domain. Further structure-guided biochemical analysis reveals that the Tom22 cytosolic domain is responsible for binding to the presequence, and the helix H1 is critical for this binding. Altogether, our results provide insights into the functional mechanism of the TOM complex recognizing and transferring preproteins across the mitochondrial membrane.
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DOI：
10.1126/science.abe9403
发表时间：
2020-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
通讯作者：
Krogan NJ
影响因子：
11.4
作者：
Bolliger, L;Junne, T;Lithgow, T
通讯作者：
Lithgow, T
蛋白质组分析前样品制备的蛋白质沉淀方法的比较。
影响因子：
4.1
作者：
Jiang, L;He, L;Fountoulakis, M
通讯作者：
Fountoulakis, M
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
64.5
作者：
Bausewein, Thomas;Mills, Deryck J.;Kuehlbrandt, Werner
通讯作者：
Kuehlbrandt, Werner