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Journal Article

Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients

MPS-Authors
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Bräuning,  Bastian
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Prabu,  Jesuraj Rajan
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons213292

Schulman,  Brenda A.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Fulltext (public)

elife-62611-v3.pdf
(Publisher version), 10MB

Supplementary Material (public)

elife-62611-figures-v3.pdf
(Supplementary material), 47MB

Citation

Miller-Vedam, L. E., Bräuning, B., Popova, K. D., Oakdale, N. T. S., Bonnar, J. L., Prabu, J. R., et al. (2020). Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients. eLife, 9: e62611. doi:10.7554/eLife.62611.


Cite as: http://hdl.handle.net/21.11116/0000-0008-0B0C-0
Abstract
Membrane protein biogenesis in the endoplasmic reticulum (ER) is complex and failure-prone. The ER membrane protein complex (EMC), comprising eight conserved subunits, has emerged as a central player in this process. Yet, we have limited understanding of how EMC enables insertion and integrity of diverse clients, from tail-anchored to polytopic transmembrane proteins. Here, yeast and human EMC cryo-EM structures reveal conserved intricate assemblies and human-specific features associated with pathologies. Structure-based functional studies distinguish between two separable EMC activities, as an insertase regulating tail-anchored protein levels and a broader role in polytopic membrane protein biogenesis. These depend on mechanistically coupled yet spatially distinct regions including two lipid-accessible membrane cavities which confer client-specific regulation, and a non-insertase EMC function mediated by the EMC lumenal domain. Our studies illuminate the structural and mechanistic basis of EMC's multifunctionality and point to its role in differentially regulating the biogenesis of distinct client protein classes.