利用 AlphaFold 系统发现蛋白质相互作用界面并进行实验验证。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Systems Biology Pub Date : 2024-02-01 Epub Date: 2024-01-15 DOI:10.1038/s44320-023-00005-6
Chop Yan Lee, Dalmira Hubrich, Julia K Varga, Christian Schäfer, Mareen Welzel, Eric Schumbera, Milena Djokic, Joelle M Strom, Jonas Schönfeld, Johanna L Geist, Feyza Polat, Toby J Gibson, Claudia Isabelle Keller Valsecchi, Manjeet Kumar, Ora Schueler-Furman, Katja Luck
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引用次数: 0

摘要

蛋白质相互作用的结构解析有助于机理和功能研究以及疾病变异的解释。然而,由于我们缺乏大规模的计算和实验工具,大多数蛋白质相互作用的结构数据仍然缺失。这对于由发生在蛋白质无序区域的短线性基团介导的相互作用来说尤其如此。我们发现,当使用小的蛋白质片段作为输入时,AlphaFold-Multimer 可以高灵敏度地预测结构域-基元相互作用的结构,但特异性有限。当使用长蛋白质片段或全长蛋白质时,灵敏度大幅下降。我们定义了一种特别适合预测结构域-结构基元界面的蛋白质片段策略,并将其应用于与神经发育障碍有关的人类蛋白质之间的相互作用。我们还通过实验进一步证实了 FBXO23-STX1B、STX1B-VAMP2、ESRRG-PSMC5、PEX3-PEX19、PEX3-PEX16 和 SNRPB-GIGYF1 的相互作用,为不同的生物过程提供了新的分子见解。我们的工作凸显了令人兴奋的前景,但也揭示了明显的局限性和未来发展的需要,以最大限度地提高 Alphafold-Multimer 在界面预测方面的能力。
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Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation.

Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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