Identification of Oxa1 Homologs Operating in the Eukaryotic Endoplasmic Reticulum

Abstract

SummaryMembers of the evolutionarily conserved Oxa1/Alb3/YidC family mediate membrane protein biogenesis at the mitochondrial inner membrane, chloroplast thylakoid membrane, and bacterial plasma membrane, respectively. Despite their broad phylogenetic distribution, no Oxa1/Alb3/YidC homologs are known to operate in eukaryotic cells outside the endosymbiotic organelles. Here, we present bioinformatic evidence that the tail-anchored protein insertion factor WRB/Get1, the “endoplasmic reticulum (ER) membrane complex” subunit EMC3, and TMCO1 are ER-resident homologs of the Oxa1/Alb3/YidC family. Topology mapping and co-evolution-based modeling demonstrate that Get1, EMC3, and TMCO1 share a conserved Oxa1-like architecture. Biochemical analysis of human TMCO1, the only homolog not previously linked to membrane protein biogenesis, shows that it associates with the Sec translocon and ribosomes. These findings suggest a specific biochemical function for TMCO1 and define a superfamily of proteins—the “Oxa1 superfamily”—whose shared function is to facilitate membrane protein biogenesis.

OXA 1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

“…Interestingly, available mRNA expression data for OXA1L suggest that brain tissue has the lowest relative expression of OXA1L and that the expression pattern is fairly similar between the various isoforms (Fig EV5). Recently, more distant homologues of Oxa1 have been identified in the eukaryotic endoplasmic reticulum, namely the DUF106‐related proteins WRB/Get1, EMC3 and TMCO1 (Anghel et al , ). Similar phylogenetic analysis yielded the same list of homologues with no additional insertase candidates ( and ).…”

The architecture of EMC reveals a path for membrane protein insertion

“…Successful biogenesis requires each of these TMDs to be moved from the aqueous phase of the cytosol into the hydrophobic core of the lipid bilayer White and Von Heijne, 2005). Although this insertion reaction can occur unassisted in vitro for some substrates (Brambillasca et al, 2005(Brambillasca et al, , 2006, insertion in the crowded cellular environment typically requires factors that facilitate the reaction to minimize off-pathway outcomes such as aggregation, mislocalization, and degradation (Anghel et al, 2017;Heinrich et al, 2000;Samuelson et al, 2000;Wang et al, 2014).…”

Biochemistry and Molecular Biology of Flaviviruses

“…181 Nonetheless, the mechanism(s) for flavivirus dependence on EMC is(are) not fully known and requires further study. The cellular function(s) of the EMC is also incompletely understood, but its requirement for proper expression of membrane resident and secreted proteins 356 and its location on the ER suggest an ER-associated chaperone-like activity. Recently, the EMC has been shown to have transmembrane domain insertase activity.…”