The structural context of posttranslational modifications at a proteome-wide scale.
The structural context of posttranslational modifications at a proteome-wide scale.
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DOI：
10.1371/journal.pbio.3001636
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发表时间：
2022-05
期刊：
影响因子：
9.8
通讯作者：
Mann, Matthias
中科院分区：
文献类型：
--
作者：
Bludau, Isabell;Willems, Sander;Zeng, Wen-Feng;Strauss, Maximilian T.;Hansen, Fynn M.;Tanzer, Maria C.;Karayel, Ozge;Schulman, Brenda A.;Mann, Matthias
最近在计算蛋白质结构预测方面的革命为整个蛋白质组提供了折叠模型，现在可以与大规模的实验数据相结合。基于质谱学(MS)的蛋白质组学已经鉴定和量化了数以万计的翻译后修饰(PTM)，其中大多数具有不确定的功能相关性。在这项研究中，我们确定了这些PTM的结构背景，并调查了如何利用这些信息来精确定位潜在的调控位点。我们的分析揭示了跨褶皱和内在无序区域的PTM发生的全球模式。我们发现，这些信息可以帮助区分调节性PTM和那些标记不正确折叠蛋白的PTM。有趣的是，人类蛋白质组包含数以千计的蛋白质，这些蛋白质具有由短而无序的区域连接的大折叠结构域，这些区域强烈富含调节的磷酸酶。其中包括众所周知的在磷酸化后引起蛋白质构象变化的蛋白激活环。这种调节机制似乎广泛存在于激酶中，但也存在于其他蛋白质家族中，如溶质载体。它不限于磷酸化，还包括泛素化和乙酰化位点。此外，我们进行了三维邻近分析，揭示了不同PTM类型的空间协同调节和潜在的PTM串扰的例子。为了使社区能够建立在这些第一次分析的基础上，我们提供了蛋白质组学数据和PTM的3D可视化工具，以及用于数据访问和处理的Python库。结合AlphaFold2的全面结构预测和关于翻译后修饰(PTM)的大规模蛋白质组学数据，基于其结构背景，揭示了PTMS的功能重要性。
The recent revolution in computational protein structure prediction provides folding models for entire proteomes, which can now be integrated with large-scale experimental data. Mass spectrometry (MS)-based proteomics has identified and quantified tens of thousands of posttranslational modifications (PTMs), most of them of uncertain functional relevance. In this study, we determine the structural context of these PTMs and investigate how this information can be leveraged to pinpoint potential regulatory sites. Our analysis uncovers global patterns of PTM occurrence across folded and intrinsically disordered regions. We found that this information can help to distinguish regulatory PTMs from those marking improperly folded proteins. Interestingly, the human proteome contains thousands of proteins that have large folded domains linked by short, disordered regions that are strongly enriched in regulatory phosphosites. These include well-known kinase activation loops that induce protein conformational changes upon phosphorylation. This regulatory mechanism appears to be widespread in kinases but also occurs in other protein families such as solute carriers. It is not limited to phosphorylation but includes ubiquitination and acetylation sites as well. Furthermore, we performed three-dimensional proximity analysis, which revealed examples of spatial coregulation of different PTM types and potential PTM crosstalk. To enable the community to build upon these first analyses, we provide tools for 3D visualization of proteomics data and PTMs as well as python libraries for data accession and processing. A combination of the comprehensive structural predictions of AlphaFold2 and large-scale proteomics data on post-translational modifications (PTMs) reveals novel insights into the functional importance of PTMs, based on their structural context.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1016/j.str.2008.10.010
发表时间：
2008-12-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Kato M;Wynn RM;Chuang JL;Tso SC;Machius M;Li J;Chuang DT
通讯作者：
Chuang DT
影响因子：
4
作者：
Flatt, Joanna F.;Stevens-Hernandez, Christian J.;Bruce, Lesley J.
通讯作者：
Bruce, Lesley J.
影响因子：
14.9
作者：
Burley SK;Bhikadiya C;Bi C;Bittrich S;Chen L;Crichlow GV;Christie CH;Dalenberg K;Di Costanzo L;Duarte JM;Dutta S;Feng Z;Ganesan S;Goodsell DS;Ghosh S;Green RK;Guranović V;Guzenko D;Hudson BP;Lawson CL;Liang Y;Lowe R;Namkoong H;Peisach E;Persikova I;Randle C;Rose A;Rose Y;Sali A;Segura J;Sekharan M;Shao C;Tao YP;Voigt M;Westbrook JD;Young JY;Zardecki C;Zhuravleva M
通讯作者：
Zhuravleva M
影响因子：
16.6
作者：
Hansen FM;Tanzer MC;Brüning F;Bludau I;Stafford C;Schulman BA;Robles MS;Karayel O;Mann M
通讯作者：
Mann M