Specificity of lipid transfer proteins: An in vitro story

Lipids, which are highly diverse, are finely distributed between organelle membranes and the plasma membrane (PM) of eukaryotic cells. As a result, each compartment has its own lipid composition and molecular identity, which is essential for the functional fate of many proteins. This distribution of lipids depends on two main processes: lipid synthesis, which takes place in different subcellular regions, and the transfer of these lipids between and across membranes. This review will discuss the proteins that carry lipids throughout the cytosol, called LTPs (Lipid Transfer Proteins). More than the modes of action or biological roles of these proteins, we will focus on the in vitro strategies employed during the last 60 years to address a critical question: What are the lipid ligands of these LTPs? We will describe the extent to which these strategies, combined with structural data and investigations in cells, have made it possible to discover proteins, namely ORPs, Sec14, PITPs, STARDs, Ups/PRELIs, START-like, SMP-domain containing proteins, and bridge-like LTPs, which compose some of the main eukaryotic LTP families, and their lipid ligands. We will see how these approaches have played a central role in cell biology, showing that LTPs can connect distant metabolic branches, modulate the composition of cell membranes, and even create new subcellular compartments.