Structure of the ER membrane complex, a transmembrane-domain insertase

The endoplasmic reticulum (ER) membrane complex (EMC) cooperates with the Sec61 translocon to co-translationally insert a transmembrane helix (TMH) of many multi-pass integral membrane proteins into the ER membrane, and it is also responsible for inserting the TMH of some tail-anchored proteins 1 –...

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Vydané v:	Nature (London) Ročník 584; číslo 7821; s. 475 - 478
Hlavní autori:	Bai, Lin, You, Qinglong, Feng, Xiang, Kovach, Amanda, Li, Huilin
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 20.08.2020 Nature Publishing Group
Predmet:	101/28 101/58 14/19 631/45/173 631/535/1258/1259 631/80/2023/2022 82/16 82/83 Binding Sites Conservation Cryoelectron Microscopy Electron microscopy Endoplasmic reticulum Endoplasmic Reticulum - chemistry Endoplasmic Reticulum - enzymology Endoplasmic Reticulum - ultrastructure Evolution, Molecular Evolutionary conservation Humanities and Social Sciences Hydrophobic and Hydrophilic Interactions Insertion Integral membrane proteins Integrals Intracellular Membranes - chemistry Intracellular Membranes - enzymology Intracellular Membranes - ultrastructure Membranes Microscopy Models, Molecular multidisciplinary Multiprotein Complexes - chemistry Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Multiprotein Complexes - ultrastructure Mutation Protein Domains Protein Subunits - chemistry Protein Subunits - genetics Protein Subunits - metabolism Proteins Saccharomyces cerevisiae - chemistry Saccharomyces cerevisiae - enzymology Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - ultrastructure Saccharomyces cerevisiae Proteins - chemistry Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Saccharomyces cerevisiae Proteins - ultrastructure Science Science (multidisciplinary) Structure-function relationships Substrate Specificity Transmembrane domains Yeast
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	The endoplasmic reticulum (ER) membrane complex (EMC) cooperates with the Sec61 translocon to co-translationally insert a transmembrane helix (TMH) of many multi-pass integral membrane proteins into the ER membrane, and it is also responsible for inserting the TMH of some tail-anchored proteins 1 – 3 . How EMC accomplishes this feat has been unclear. Here we report the first, to our knowledge, cryo-electron microscopy structure of the eukaryotic EMC. We found that the Saccharomyces cerevisiae EMC contains eight subunits (Emc1–6, Emc7 and Emc10), has a large lumenal region and a smaller cytosolic region, and has a transmembrane region formed by Emc4, Emc5 and Emc6 plus the transmembrane domains of Emc1 and Emc3. We identified a five-TMH fold centred around Emc3 that resembles the prokaryotic YidC insertase and that delineates a largely hydrophilic client protein pocket. The transmembrane domain of Emc4 tilts away from the main transmembrane region of EMC and is partially mobile. Mutational studies demonstrated that the flexibility of Emc4 and the hydrophilicity of the client pocket are required for EMC function. The EMC structure reveals notable evolutionary conservation with the prokaryotic insertases 4 , 5 , suggests that eukaryotic TMH insertion involves a similar mechanism, and provides a framework for detailed understanding of membrane insertion for numerous eukaryotic integral membrane proteins and tail-anchored proteins. The cryo-electron microscopy structure of the ER membrane complex provides insight into its overall architecture, evolution and function in co-translational protein insertion.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 CONTRIBUTIONS. L.B. and H.L. conceived and designed experiments. L.B. performed most of the experiments. Q.Y, X. F., and A.K. helped with sample preparation and functional assays. L.B. and H.L. analyzed the data and wrote the manuscript.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-020-2389-3