Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes

Abstract

Lipids are distributed in a highly asymmetric fashion in different cellular membranes. Only a minority of lipids achieve their final intracellular distribution by selection into the membranes of transport vesicles. Instead, the bulk of lipid traffic is mediated by a large group of lipid transfer proteins (LTPs), which move small numbers of lipids at a time using hydrophobic cavities that stabilise lipid outside membranes. Despite the first discoveries of LTPs almost 50 years ago, most progress has been made in the last few years, leading to considerable temporal and spatial refinement in our understanding. The number of known LTPs has increased, with exciting discoveries of multimeric assemblies. Structural studies of LTPs have progressed from static crystal structures to dynamic structural approaches that show how conformational changes contribute to lipid handling at a sub-millisecond timescale. Many intracellular LTPs localise to membrane contact sites, nanoscale zones where an LTP can form either a shuttle, bridge or tube linking donor and acceptor compartments. Understanding how each lipid achieves its final destination at the molecular level allows a better explanation of the range of defects that occur in disease, with therapies being developed to target lipid transfer.

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

“…How does Atg2 transfer phospholipids from ERES to the IM? Because the MT activity is indispensable for the LT activity of Atg2, a well‐known LT system, in which LT proteins shuttle between organelles, does not appear to apply to Atg2. As described above, Atg2‐mediated LT requires the region downstream of Atg2 NR , which has been predicted to contain five repeated structures .…”

Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

“…Non-vesicular pathways exploit the dense cytoplasmic packing of organelles to enable functional alliances through inter-organelle associations. Such associations are mediated by tethering proteins, which create so-called 'contact sites' for direct channeling of metabolites, lipids and ions between organelles (Wong et al, 2019). A major challenge has been to identify the diverse array of proteins involved in generating organelle contact sites and to understand how they mediate non-vesicular transport.…”

The autophagic membrane tether ATG2A transfers lipids between membranes

“…Lipid transfer proteins can extract lipid molecules from existing membranes (Wong et al, 2018). To examine whether ATG2A has such activity, we adapted a lipid extraction assay in which liposomes containing fluorescent lipids (nitrobenzoxadiazole-conjugated PE: NBD-PE) are incubated with proteins, followed by liposome flotation to isolate the lipid-bound proteins (Kawano et al, 2018).…”

“…These recent advancements defined the role of ATG2-Atg18/WIPI4 complexes as mediators of the ERphagophore edge association but did not explain the means by which such membrane associations lead to phagophore expansion. The size, overall shape, and membrane tethering activity of ATG2A called to mind tubular lipid-transferring proteins, such as the extended synaptotagmins and the ER-mitochondrial encounter structure (ERMES) complex (AhYoung et al, 2015;Jeong, Park, Jun, & Lee, 2017;Schauder et al, 2014;Wong, Gatta, & Levine, 2018), which further led us to hypothesize that ATG2A could be a lipidtransferring protein. This hypothesis is strongly supported by a recent study reporting that VPS13 family proteins are lipid-transferring proteins (Kumar et al, 2018).…”