Cells possess specialized machinery to direct the insertion of membrane proteins into the lipid bilayer. In all organisms, the Sec61/SecYEG channel inserts most membrane proteins into the membrane in concert with various accessory subunits. Additionally, other membrane protein insertion systems have been described. In bacteria, the essential protein YidC inserts certain proteins into the plasma membrane. Eukaryotic orthologs of YidC are present in the mitochondrial inner membrane and the chloroplast thylakoid membrane (where they are called Oxa1 and Alb3 respectively) but no homologs have been described outside the endosymbiotic organelles. In eukaryotes, the Get1/2 complex inserts a subset of proteins with a single transmembrane domain at their C-terminus, but whether this pathway is conserved in prokaryotes is also unclear. Here, I present evidence that bacterial YidC and eukaryotic Get1 are both members of a superfamily of membrane protein biogenesis factors which I refer to as the Oxa1 superfamily. This superfamily includes a group of archaeal proteins annotated as DUF106, and two eukaryotic proteins named EMC3 and TMCO1. All superfamily members share a core membrane topology and structural fold in addition to key functional features. Archaeal superfamily members, like bacterial YidC, interact specifically with ribosomes translating a YidC substrate. Of the eukaryotic proteins, I show that the previously poorly understood TMCO1 protein functions in membrane protein biogenesis. TMCO1 associates with ribosomes translating multipass membrane proteins and functions in a complex with the Sec61 channel, some translocon accessory components and a group of poorly understood protein quality control factors. This work establishes a new paradigm for the evolution of membrane protein biogenesis factors and defines a biochemical function for TMCO1, paving the way for future mechanistic analysis of this novel pathway.




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