Klose Carolin J, Meighen-Berger Kevin M, Kulke Martin, Parr Marina, Steigenberger Barbara, Zacharias Martin, Frishman Dmitrij, Feige Matthias J
Department of Bioscience, TUM School of Natural Sciences, Center for Functional Protein Assemblies (CPA), Technical University of Munich, Garching, Germany.
Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
Nat Commun. 2025 Aug 2;16(1):7097. doi: 10.1038/s41467-025-62109-x.
Structure formation of membrane proteins is error-prone and thus requires chaperones that oversee this essential process in cell biology. The ER membrane protein complex (EMC) is well-defined as a transmembrane domain (TMD) insertase. In this study, we characterize an additional chaperone function of the EMC. We use interactomics and systematic studies with model proteins to comprehensively define client features for this EMC chaperone mode. Based on this data, we develop a machine learning-based tool for client prediction. Mechanistically, our study reveals that the EMC engages TMDs via its EMC1 subunit and modulates their orientation within the lipid bilayer. Productive TMD assembly reduces binding to the EMC chaperone site. Taken together, our study provides detailed insights into an EMC chaperone function, further establishing the role of the EMC as a multifunctional molecular machine in membrane protein biogenesis.
膜蛋白的结构形成容易出错，因此需要伴侣蛋白来监督细胞生物学中的这一关键过程。内质网（ER）膜蛋白复合物（EMC）被明确为一种跨膜结构域（TMD）插入酶。在本研究中，我们表征了EMC的另一种伴侣蛋白功能。我们利用相互作用组学以及对模型蛋白的系统性研究，全面定义了这种EMC伴侣蛋白模式的底物特征。基于这些数据，我们开发了一种基于机器学习的底物预测工具。从机制上讲，我们的研究表明，EMC通过其EMC1亚基与TMD结合，并调节它们在脂质双层中的方向。有效的TMD组装减少了与EMC伴侣蛋白位点的结合。综上所述，我们的研究为EMC的伴侣蛋白功能提供了详细的见解，进一步确立了EMC作为膜蛋白生物合成中多功能分子机器的作用。
