The ER membrane protein complex is a transmembrane domain insertase

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Science  26 Jan 2018:
Vol. 359, Issue 6374, pp. 470-473
DOI: 10.1126/science.aao3099

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A new way into the ER

Membrane-embedded proteins are highly diverse in topology, physical characteristics, and location. This diversity necessitates multiple pathways for their effective membrane insertion. Guna et al. found that a widely conserved protein complex is responsible for inserting a subset of membrane proteins into the endoplasmic reticulum (ER) membrane (see the Perspective by Fry and Clemons Jr.). This ER membrane protein complex (EMC) inserts transmembrane domains whose topology and hydrophobicity preclude effective recognition by other insertion factors. This finding helps explain why the loss of EMC causes ER stress and altered protein trafficking.

Science, this issue p. 470; see also p. 390


Insertion of proteins into membranes is an essential cellular process. The extensive biophysical and topological diversity of membrane proteins necessitates multiple insertion pathways that remain incompletely defined. Here we found that known membrane insertion pathways fail to effectively engage tail-anchored membrane proteins with moderately hydrophobic transmembrane domains. These proteins are instead shielded in the cytosol by calmodulin. Dynamic release from calmodulin allowed sampling of the endoplasmic reticulum (ER), where the conserved ER membrane protein complex (EMC) was shown to be essential for efficient insertion in vitro and in cells. Purified EMC in synthetic liposomes catalyzed the insertion of its substrates in a reconstituted system. Thus, EMC is a transmembrane domain insertase, a function that may explain its widely pleiotropic membrane-associated phenotypes across organisms.

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