Quantitative Models of Lipid Transfer and Membrane Contact Formation

Abstract

Lipid transfer proteins (LTPs) transfer lipids between different organelles, and thus play key roles in lipid homeostasis and organelle dynamics. The lipid transfer often occurs at the membrane contact sites (MCS) where two membranes are held within 10–30 nm. While most LTPs act as a shuttle to transfer lipids, recent experiments reveal a new category of eukaryotic LTPs that may serve as a bridge to transport lipids in bulk at MCSs. However, the molecular mechanisms underlying lipid transfer and MCS formation are not well understood. Here, we first review two recent studies of extended synaptotagmin (E-Syt)-mediated membrane binding and lipid transfer using novel approaches. 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 membranes of similar composition and/or lipid partitioning among membranes of distinct composition can explain lipid transfer against a concentration gradient widely observed for LTPs. We predict that selective transport of lipids, but not membrane proteins, by bridge LTPs leads to osmotic membrane tension by analogy to the osmotic pressure across a semipermeable membrane. A gradient of such 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. Overall, the quantitative models may help clarify the mechanisms of LTP-mediated MCS formation and lipid transfer.

In situ structural analysis reveals membrane shape transitions during autophagosome formation

“…Note that this model assumes a sufficient abundance of curvature generators stabilizing the rim ( 17 ) and a continued flow of lipids into the phagophore during growth. Possible drivers for this directional transport are local lipid synthesis in the ER ( 45 ), a high local concentration of Atg8 in the phagophore favoring lipid influx in an osmosis-like process ( 50 ), or differences in membrane curvature ( Fig. 4 E ).…”

Sequence Analysis and Structural Predictions of Lipid Transfer Bridges in the Repeating Beta Groove (RBG) Superfamily Reveal Past and Present Domain Variations Affecting Form, Function and Interactions of VPS13, ATG2, SHIP164, Hobbit and Tweek

“…Cytoplasmic bridge-like LTPs with a similar hydrophobic groove were then discovered in eukaryotes: VPS13 and ATG2 (3000–4000 aa and 1500–2000 aa respectively) are distantly related proteins that form rods approximately 20 and 15 nm long (Figure 1A) (Kumar et al, 2018; Osawa and Noda, 2019; Valverde et al, 2019; Ugur et al, 2020; Dziurdzik and Conibear, 2021; Leonzino et al, 2021). VPS13 and ATG2 transfer phospholipids efficiently in vitro (von Bülow and Hummer, 2020; Zhang et al, 2022), and they are required for rapid growth of the yeast prospore membrane and autophagosomes (respectively), both of which have few embedded proteins, indicating delivery of lipid in bulk (Lees and Reinisch, 2020). A pivotal observation is that VPS13 function is inhibited by converting the lining of one segment of the rod from hydrophobic to charged residues (Li et al, 2020) (Figure 1A).…”

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

“…[ 106 ] Beyond regulation of the tethers themselves, alterations in the products (e.g., lipids and Ca 2+ ) which are transferred at MCS can also influence the formation and function of MCS. [ 107 ] MCS connect numerous different biochemical pathways, in particular in lipid metabolism, where reactions are often initiated in one organelle with subsequent steps occurring within different organelles. Therefore, MCS represent control points at which decisions on the direction of metabolic flux through a pathway may be determined (e.g., ER, mitochondria, peroxisomes, lysosomes and lipid droplets in metabolism of fatty acids).…”