The endoplasmic reticulum membrane protein complex (EMC) is a putative endoplasmic reticulum-resident membrane protein (co-)chaperone. The EMC is evolutionarily conserved in eukaryotes (animals, plants, and fungi), and its initial appearance might reach back to the last eukaryotic common ancestor (LECA). Many aspects of mEMC biology and molecular function remain to be studied.
Composition and structure
The EMC consists of up to 10 subunits (EMC1 - EMC4, MMGT1, EMC6 - EMC10), of which only two (EMC8/9) are homologous proteins. Seven out of ten (EMC1, EMC3, EMC4, MMMGT1, EMC6, EMC7, EMC10) subunts are predicted to contain at least one transmembrane domain (TMD), whereas EMC2, EMC8 and EMC9 do not contain any predicted transmembrane domains are herefore likely to interact with the rest of the EMC on the cytosolic face of the endoplasmic reticulum (ER). EMC proteins are thought to be present in the mature complex in a 1:1 stoichiometry.
Subunit primary structure
The majority of EMC proteins (EMC1/3/4/MMGT1/6/7/10) contain at least one predicted TMD. EMC1, EMC7 and EMC10 contain an N-terminal signal sequence.
EMC1
EMC1, also known as KIAA0090, contains a single TMD (aa 959-979) and Pyrroloquinoline quinone (PQQ)-like repeats (aa 21-252), which could form a β-propeller domain. The TMD is part of a domain a larger domain (DUF1620). The functions of the PQQ and DUF1620 domains in EMC1 remain to be determined.
EMC2
EMC2 (TTC35) harbours three tetratricopeptide repeats (TPR1/2/3). TPRs have been shown to mediate protein-protein interactions and can be found in a large variety of proteins of diverse function. The function of TPRs in EMC2 is unknown.
EMC8 and EMC9
EMC8 and EMC9 show marked sequence identity (44.72%) on the amino acid level. Both proteins are members of the UPF0172 family, a member of which (e.g. TLA1) are involved in regulating the antenna size of chlorophyll-a.
Posttranslational modifications
Several subunits of the mammalian EMC (mEMC) are posttranslationally modified. EMC1 contains three predicted N-glcosylation sites at positions 370, 818, and 913. EMC10 features a predicted N-glycosylation consensus motif at position 182.
Evolutionary conservation
EMC proteins are evolutionarily conserved in eukaryotes. No homologues are reported in prokaryotes. Therefore, the EMC has been suggested to have its evolutionary roots in the last eukaryote common ancestor (LECA).
Function
Protein folding and degradation at the ER
The EMC was first identified in a genetic screen in yeast for factors involved in protein folding in the ER. Accordingly, deletion of individual EMC subunits correlates with the induction of an ER stress response in various model organisms. However, it is worth noting that in human osteosarcoma cells (U2OS cells), deletion of EMC6 does not appear to cause ER stress. When overexpressed, several subunits of the mammalian EMC orthologue (mEMC) have been found to physically interact with ERAD components (UBAC2, DER1, DER2) Genetic screens in yeast have shown EMC subunits to be enriched in alongside ERAD genes. Taken together, these findings imply a role of the mEMC in protein homeostasis.
Chaperone
Maturation of polytopic membrane proteins
Several lines of evidence implicate the EMC in promoting the maturation of polytopic membrane proteins. The EMC is necessary to correctly and efficiently insert the first transmembrane domain (also called the signal anchor) of G-protein coupled receptors (GPCRs) such as the beta-adrenergic receptor. Determining features of transmembrane domains that favour EMC involvement seem to be moderate hydrophobicity and ambiguous distribution of TMD flanking charges.
The substrate spectrum of the EMC appears to extend beyond GPCRs. Unifying properties of putative EMC clients are the presence of unusually hydrophilic transmembrane domains containing charged residues. However, mechanistic detail of how the EMC assists in orienting and inserting such problematic transmembrane domains is lacking. In many cases, evidence implicating the EMC in the biogenesis of a certain protein consists of co-depletion when individual subunts of the EMC are disrupted.
A number of putative EMC clients are listed below, but the manner in which the EMC engages them and whether they directly or indirectly depend on the EMC merits further investigation: