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Role of a holo-insertase complex in the biogenesis of biophysically diverse ER membrane proteins. | LitMetric

Role of a holo-insertase complex in the biogenesis of biophysically diverse ER membrane proteins.

Mol Cell

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Ave., Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address:

Published: September 2024

AI Article Synopsis

  • - Mammalian membrane proteins must be accurately inserted and folded in the endoplasmic reticulum (ER) to perform their important functions, prompting research into their biogenesis, particularly G-protein-coupled receptors (GPCRs).
  • - The study highlighted the significant role of the endoplasmic reticulum membrane protein complex (EMC) and introduced a dual-guide approach to uncover genetic factors influencing the EMC.
  • - Findings revealed that the back of the Sec61 complex interacts with the EMC, leading to a new understanding that different insertases may be required for different membrane proteins, suggesting a coordinated system for their biogenesis in human cells.

Article Abstract

Mammalian membrane proteins perform essential physiologic functions that rely on their accurate insertion and folding at the endoplasmic reticulum (ER). Using forward and arrayed genetic screens, we systematically studied the biogenesis of a panel of membrane proteins, including several G-protein-coupled receptors (GPCRs). We observed a central role for the insertase, the ER membrane protein complex (EMC), and developed a dual-guide approach to identify genetic modifiers of the EMC. We found that the back of Sec61 (BOS) complex, a component of the multipass translocon, was a physical and genetic interactor of the EMC. Functional and structural analysis of the EMC⋅BOS holocomplex showed that characteristics of a GPCR's soluble domain determine its biogenesis pathway. In contrast to prevailing models, no single insertase handles all substrates. We instead propose a unifying model for coordination between the EMC, the multipass translocon, and Sec61 for the biogenesis of diverse membrane proteins in human cells.

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Source
http://dx.doi.org/10.1016/j.molcel.2024.08.005DOI Listing

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