Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients
Copyright policy )Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients
AbstractMembrane 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 revealed at least two separable EMC activities, as an insertase regulating tail-anchored protein levels and as a polytopic membrane protein holdase chaperone. These depend on mechanistically coupled yet spatially distinct regions including two lipid-accessible membrane cavities which confer client-specific regulation, and a novel, 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.
- Max Planck Society Germany
- University of California, San Francisco United States
- University of California, Berkeley United States
- Massachusetts Institute of Technology United States
- Max Planck Institute of Biochemistry Germany
Biomedical and clinical sciences, S. cerevisiae, Endoplasmic Reticulum, cell biology, 31 Biological sciences (for-2020), EMC, structural biology, Sequence Alignment (mesh), Biology (General), Humans (mesh), Membrane Proteins (mesh), Blotting, membrane protein biogenesis, Generic health relevance (hrcs-hc), Q, R, Biological Sciences, endoplasmic reticulum, Endoplasmic Reticulum (mesh), insertase, Medicine, Western, Protein Structure, Saccharomyces cerevisiae Proteins, QH301-705.5, 1.1 Normal biological development and functioning, Saccharomyces cerevisiae Proteins (mesh), Science, Blotting, Western, 0601 Biochemistry and Cell Biology (for), 610, Saccharomyces cerevisiae, 42 Health sciences (for-2020), Western (mesh), molecular biophysics, Humans, human, Saccharomyces cerevisiae (mesh), chaperone holdase, Intracellular Membranes (mesh), 1.1 Normal biological development and functioning (hrcs-rac), 31 Biological Sciences (for-2020), electron microscopy, Health sciences, Membrane Proteins, Cell Biology, Intracellular Membranes, 3101 Biochemistry and Cell Biology (for-2020), Protein Structure, Tertiary, Tertiary (mesh), 32 Biomedical and clinical sciences (for-2020), Biochemistry and Cell Biology, Generic health relevance, Sequence Alignment, Tertiary
Biomedical and clinical sciences, S. cerevisiae, Endoplasmic Reticulum, cell biology, 31 Biological sciences (for-2020), EMC, structural biology, Sequence Alignment (mesh), Biology (General), Humans (mesh), Membrane Proteins (mesh), Blotting, membrane protein biogenesis, Generic health relevance (hrcs-hc), Q, R, Biological Sciences, endoplasmic reticulum, Endoplasmic Reticulum (mesh), insertase, Medicine, Western, Protein Structure, Saccharomyces cerevisiae Proteins, QH301-705.5, 1.1 Normal biological development and functioning, Saccharomyces cerevisiae Proteins (mesh), Science, Blotting, Western, 0601 Biochemistry and Cell Biology (for), 610, Saccharomyces cerevisiae, 42 Health sciences (for-2020), Western (mesh), molecular biophysics, Humans, human, Saccharomyces cerevisiae (mesh), chaperone holdase, Intracellular Membranes (mesh), 1.1 Normal biological development and functioning (hrcs-rac), 31 Biological Sciences (for-2020), electron microscopy, Health sciences, Membrane Proteins, Cell Biology, Intracellular Membranes, 3101 Biochemistry and Cell Biology (for-2020), Protein Structure, Tertiary, Tertiary (mesh), 32 Biomedical and clinical sciences (for-2020), Biochemistry and Cell Biology, Generic health relevance, Sequence Alignment, Tertiary
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