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3.A.27.  The Endoplasmic Reticulum Membrane Protein Insertion Complex (EMC) Family

Guna et al. 2018 found that known membrane insertion pathways fail to effectively engage tail-anchored membrane proteins with moderately hydrophobic C-terminal 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 (Guna et al. 2018). This family can be considered to be the second C-terminal Tail-Anchored Membrane Protein Biogenesis/Insertion Complex Family, the first having TC# 3.A.21. 

The ten known proteins of the EMC are EMC1 - EMC10.  These proteins have sizes between 110 and 993 aas, seven of them having sizes between 180 and 300 aas in humans (see 3.A.27.1.1).  These proteins have between ) and 3 TMSs each.  None of them are clearly homologous to any of the proteins in TCDB based on sequence similarity.  However, Guna et al. 2018 reported that EMC3 is distantly related to the yeast Get1 protein and the mammalian TRC40 protein, subunits of the insertase for the TRC pathway (Wang et al. 2014) (see TC#s 3.A.19 and 3.A.21). Get1 and EMC3 may have evolved from the ancestral prokaryotic insertase of the YidC family as claimed by Guna et al., 2018,  The EMC has been genetically implicated in several membrane-associated processes such as quality control, trafficking, protein maturation, and lipid homeostasis (Jonikas et al. 2009; Christianson et al. 2011).

The reaction belived to be catalyzed by the EMC complex is:

C-terminal tail anchored protein with a moderately hydrophobic TMS (associated with calmodulin in the cytoplasm) → C-terminal tail anchored protein with a moderately hydrophobic TMS (anchored to the ER membrane).



References associated with 3.A.27 family:

Christianson, J.C., J.A. Olzmann, T.A. Shaler, M.E. Sowa, E.J. Bennett, C.M. Richter, R.E. Tyler, E.J. Greenblatt, J.W. Harper, and R.R. Kopito. (2011). Defining human ERAD networks through an integrative mapping strategy. Nat. Cell Biol. 14: 93-105. 22119785
Guna, A., N. Volkmar, J.C. Christianson, and R.S. Hegde. (2018). The ER membrane protein complex is a transmembrane domain insertase. Science 359: 470-473. 29242231
Jonikas, M.C., S.R. Collins, V. Denic, E. Oh, E.M. Quan, V. Schmid, J. Weibezahn, B. Schwappach, P. Walter, J.S. Weissman, and M. Schuldiner. (2009). Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science 323: 1693-1697. 19325107
Wang, F., C. Chan, N.R. Weir, and V. Denic. (2014). The Get1/2 transmembrane complex is an endoplasmic-reticulum membrane protein insertase. Nature 512: 441-444. 25043001