Lipid trafficking: Exchange by ORDer

Nature Reviews Molecular Cell Biology 11, 86-87, (February 2010) [doi:10.1038/nrm2840]

The proper distribution of sterols between cellular membranes is controlled by vesicular- and protein-mediated transfer pathways. Lipid transfer proteins (LTPs) reversibly bind lipids and transport them between membranes, but it is not clear how the movement occurs or how it is regulated. Prinz and colleagues now show that by simultaneously contacting two membranes, the core lipid-binding domain of oxysterol-binding protein (OSBP)-related proteins (ORPs) — a family of LTPs — 'senses' the composition of one membrane to regulate sterol transfer at the other.

ORPs contain an OSBP-related domain (ORD) with a sterol-binding pocket. Some ORDs are thought to also bind phosphatidylinositol phosphates (PtdInsPs) at another surface. The authors show that ORDs purified from yeast cause aggregation of liposomes (structures made of phospholipids), suggesting that this domain can bind two membranes simultaneously. Using the representative ORP Osh4 (also known as Kes1), which consists almost entirely of an ORD, they identified a second membrane-binding surface — distal to the sterol-binding pocket — that was necessary for liposome aggregation.

The efficiency of sterol extraction or delivery by Osh4, measured fluorometrically, was proportional to the concentration of the acidic phospholipid phosphatidylserine (PtdS) in the liposomes. Furthermore, the authors confirmed an earlier observation that sterol transfer by wild-type Osh4 is enhanced by small amounts of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P₂) in either the donor or acceptor liposomes. However, when the distal membrane-binding surface was mutated, Osh4 activity was not proportional to PtdS level and was not stimulated by PtdIns(4,5)P₂. This suggests that the second membrane-binding surface senses lipid composition at one membrane to regulate sterol transfer at the other.

Sterol transfer by Osh4 was reduced when diffusion of the protein was limited, suggesting that it would be more rapid between closely apposed membranes. Covalent attachment of Osh4 to the liposomes did not prevent sterol transfer, provided that the linker used was long enough to allow some freedom of movement. These data support a model in which ORDs at closely apposed membranes sense the PtdInsP composition of one side through their distal lipid-binding site, and pivot between the membranes to deliver or extract sterols in response. This would link PtdIns signalling pathways to changes in membrane composition, with many potential downstream signalling consequences.

This new mechanism of regulated lipid transfer could transmit signals between organelles, and the focus now will be to identify proteins that work in concert with ORPs.

Emma Leah