Quantitative Models of Lipid Transfer and Membrane Contact Formation

Abstract

AbstractLipid transfer proteins (LTPs) transport lipids between different organelles in the cell, and thus play key roles in lipid homeostasis and organelle dynamics. The lipid transfer process often occurs at the membrane contact sites (MCS), where two membranes are held within 10-30 nm by LTPs and other membrane tethering factors. While most LTPs act as a shuttle to transfer lipids via their lipid-binding cavities, recent experiments reveal a new category of eukaryotic LTPs that may serve as a bridge to transport lipids in bulk at MCSs, leading to membrane expansion involved in organelle biogenesis. However, the molecular mechanisms underlying lipid transfer and membrane contact formation are not well understood. Here, we first review two recent studies of extended synaptotagmin (E-Syt)-mediated membrane binding and lipid transfer using optical tweezers and DNA origami, respectively. Then we describe mathematical models to quantify the kinetics of lipid transfer by shuttle LTPs based on a lipid exchange mechanism. We find that simple lipid mixing among similar membranes and/or lipid partitioning among different membranes can explain lipid transfer against a concentration gradient widely observed for LTPs. Based on these calculations, we hypothesize that lipid exchange is a general mechanism for lipid transfer by shuttle LTPs. We predict that selective transport of lipids, but not membrane proteins, by bridge LTPs leads to osmotic membrane tension in analog to the osmotic pressure across a semipermeable membrane. A gradient of such osmotic membrane tension and the conventional membrane tension may drive bulk lipid flow through bridge LTPs at a speed consistent with the fast membrane expansion observed in vivo. Finally, we discuss the implications of membrane tension and lipid transfer in organelle biogenesis and membrane morphologies. Overall, the quantitative models may help clarify the mechanisms of MCS formation by E-Syts and lipid transfer by LTPs in general.