EMC3

EMC3 (ER membrane protein complex subunit 3; also TMEM111) is a 261-residue polytopic ER membrane protein with three transmembrane helices and a lumenal N-terminus, and is the catalytic insertase subunit of the ER membrane protein complex (EMC), a conserved nine- to ten-subunit transmembrane-domain insertase and membrane-protein chaperone of the endoplasmic reticulum. EMC3 belongs to the Oxa1/YidC/Get1 insertase superfamily and is a distant homolog of the tail-anchored-protein insertase Get1; together with the small subunit EMC6 it forms the membrane-embedded hydrophilic vestibule through which substrate transmembrane domains are inserted. A methionine-rich cytosolic loop of EMC3 is required for substrate engagement, and structure-guided mutations of EMC3 residues lining the vestibule (e.g. Arg-31, the Met-rich loop, Arg-180) reduce client insertion without disrupting complex assembly, demonstrating that EMC3 provides the substrate-conducting active site. As part of the EMC, EMC3 enables the energy-independent insertion of newly synthesized membrane proteins into the ER membrane, with a preference for transmembrane domains that are weakly hydrophobic or carry destabilizing charged or aromatic residues. It mediates post-translational insertion of tail-anchored proteins and cotranslational insertion and N-exo topogenesis of multipass membrane proteins, including the first transmembrane domain of G protein-coupled receptors, in cooperation with the Sec61 translocon. EMC3 is broadly expressed and resides in the ER membrane.