An origin for a eukaryotic lipid transfer protein fold in Asgard archaea

The evolution of eukaryotic cells necessitated the advent of machinery to transport phospholipids, the molecular building blocks of cell membranes, to support organelle proliferation. Eukaryotes share several classes of highly conserved lipid transfer proteins (LTP) that associate with donor membranes, bind individual phospholipids, and shuttle them to acceptor membranes. Because cells lacking organelles do not require extensive lipid transport networks, it is not known if this machinery pre-dated eukaryotic organelles or had to evolve alongside them. Here we describe a class of phospholipid transporters in the Asgard achaea that share key structural and functional similarities to eukaryotic LTPs in the START domain superfamily. Asgards contain three classes of START proteins, StarAsg1-3, which are conserved across most Asgard phyla. Of these, StarAsg1 family proteins contain the predicted structural features necessary for lipid transfer: large, hydrophobic binding pockets lined with amphipathic motifs for membrane docking. In contrast, StarAsg2 and StarAsg3 family proteins contain smaller binding cavities and minimal predicted membrane interactions. StarAsg1 from Lokiarchaeia interacts with anionic membranes both in vitro and in yeast cells, where it binds phospholipids. Lipid transfer assays show that StarAsg1 from Lokiarchaeia can exchange several classes of phospholipids between membranes, as eukaryotic START LTPs do. Structural phylogeny of START domains across the tree of life suggest that eukaryotic LTPs could share a common ancestry with StarAsg1 homologs, while StarAsg2 and StarAsg3 form a monophyletic group with a eukaryotic heat shock protein co-chaperone. We propose that the presence of inter-membrane lipid transporters in the ancestors of eukaryotic cells could have facilitated the development of complex intracellular organelles.