Structural basis of an endoplasmic reticulum EMC:Spf1 insertase-dislocase complex.
11 affiliations
- 1Center for Functional Protein Assemblies (CPA), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany. [email protected].
- 2Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany. [email protected].
- 3Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
- 4Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
- 5Center for Biochemistry and Center for Molecular Medicine Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
- 6Scala Biodesign, Tel Aviv, Israel.
- 7Center for Functional Protein Assemblies (CPA), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany.
- 8Mass Spectrometry Core Facility, Max Planck Institute of Biochemistry, Martinsried, Germany.
- 9Center for Functional Protein Assemblies (CPA), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany. [email protected].
- 10Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany. [email protected].
- 11Center for Functional Protein Assemblies (CPA), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany. [email protected].
Abstract
Most eukaryotic membrane proteins are inserted into the membrane at the endoplasmic reticulum (ER). This essential process relies on molecular quality control machineries to prevent mistargeting and incorrect structure formation. Here, we show that the ER membrane protein complex (EMC) forms an evolutionarily conserved supercomplex with the P5A-ATPase Spf1/ATP13A1. Biochemical, structural and cellular analyses demonstrate that the EMC and Spf1 associate in a stoichiometric manner and retain their individual catalytic activities, the transmembrane domain (TMD) insertase function of the EMC and the TMD dislocase activity of Spf1. Our cryo-electron microscopy structures show that the EMC insertase cavity and the Spf1 dislocase cleft are positioned in close proximity within the membrane and reveal that the ATPase cycle of Spf1 remodels the interface between the two machineries and alters cytoplasmic accessibility of both substrate-binding cavities. Together, our study provides structural insights into how membrane protein insertion and extraction machineries can be spatially coordinated at the ER membrane, suggesting that functionally distinct proteostasis factors can assemble into hubs to support membrane protein biogenesis and quality control.
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BibTeX
@article{klose2026structural,
title = {{Structural basis of an endoplasmic reticulum EMC:Spf1 insertase-dislocase complex.}},
author = {Carolin J Klose and J Rajan Prabu and Emma J Fenech and Bastian Bräuning and Ida Baydar and Barbara Steigenberger and Susanne von Gronau and Sivan Arad and Christine R Langlois and Maya Schuldiner and Brenda A Schulman and Matthias J Feige},
journal = {Nature structural \& molecular biology},
year = {2026},
month = oct,
doi = {10.1038/s41594-026-01883-8},
url = {https://europepmc.org/article/MED/42870022},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structural basis of an endoplasmic reticulum EMC:Spf1 insertase-dislocase complex.
AU - Carolin J Klose
AU - J Rajan Prabu
AU - Emma J Fenech
AU - Bastian Bräuning
AU - Ida Baydar
AU - Barbara Steigenberger
AU - Susanne von Gronau
AU - Sivan Arad
AU - Christine R Langlois
AU - Maya Schuldiner
AU - Brenda A Schulman
AU - Matthias J Feige
PY - 2026
DA - 2026/10/13
JO - Nature structural & molecular biology
DO - 10.1038/s41594-026-01883-8
UR - https://europepmc.org/article/MED/42870022
AB - Most eukaryotic membrane proteins are inserted into the membrane at the endoplasmic reticulum (ER). This essential process relies on molecular quality control machineries to prevent mistargeting and incorrect structure formation. Here, we show that the ER membrane protein complex (EMC) forms an evolutionarily conserved supercomplex with the P5A-ATPase Spf1/ATP13A1. Biochemical, structural and cellular analyses demonstrate that the EMC and Spf1 associate in a stoichiometric manner and retain their individual catalytic activities, the transmembrane domain (TMD) insertase function of the EMC and the TMD dislocase activity of Spf1. Our cryo-electron microscopy structures show that the EMC insertase cavity and the Spf1 dislocase cleft are positioned in close proximity within the membrane and reveal that the ATPase cycle of Spf1 remodels the interface between the two machineries and alters cytoplasmic accessibility of both substrate-binding cavities. Together, our study provides structural insights into how membrane protein insertion and extraction machineries can be spatially coordinated at the ER membrane, suggesting that functionally distinct proteostasis factors can assemble into hubs to support membrane protein biogenesis and quality control.
SN - 1545-9993
SN - 1545-9985
ER -