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Research Paper|Volume 16, Issue 6|pp 5501—5525

Structural insights into human EMC and its interaction with VDAC

Mingyue Li1,2, Chunli Zhang1,2, Yuntao Xu1,2, Shaobai Li1,2, Chenhui Huang1,2, Jian Wu1,2, Ming Lei1,2,3
  • 1Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
  • 2Shanghai Institute of Precision Medicine, Shanghai 200125, China
  • 3State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
* Equal contribution
Received: November 6, 2023Accepted: February 8, 2024Published: March 15, 2024
https://doi.org/10.18632/aging.205660

Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved, multi-subunit complex acting as an insertase at the ER membrane. Growing evidence shows that the EMC is also involved in stabilizing and trafficking membrane proteins. However, the structural basis and regulation of its multifunctionality remain elusive. Here, we report cryo-electron microscopy structures of human EMC in apo- and voltage-dependent anion channel (VDAC)-bound states at resolutions of 3.47 Å and 3.32 Å, respectively. We discovered a specific interaction between VDAC proteins and the EMC at mitochondria-ER contact sites, which is conserved from yeast to humans. Moreover, we identified a gating plug located inside the EMC hydrophilic vestibule, the substrate-binding pocket for client insertion. Conformation changes of this gating plug during the apo-to-VDAC-bound transition reveal that the EMC unlikely acts as an insertase in the VDAC1-bound state. Based on the data analysis, the gating plug may regulate EMC functions by modifying the hydrophilic vestibule in different states. Our discovery offers valuable insights into the structural basis of EMC's multifunctionality.