Structure and function of phosphatidylcholine transfer protein (PC-TP)/StarD2

Abstract

Phosphatidylcholine transfer protein (PC-TP) is a highly specific soluble lipid binding protein that transfers phosphatidylcholine between membranes in vitro. PC-TP is a member of the steroidogenic acute regulatory protein-related transfer (START) domain superfamily. Although its biochemical properties and structure are well characterized, the functions of PC-TP in vivo remain incompletely understood. Studies of mice with homozygous disruption of the Pctp gene have largely refuted the hypothesis that this protein participates in the hepatocellular selection and transport of biliary phospholipids, in the production of lung surfactant, in leukotriene biosynthesis and in cellular phosphatidylcholine metabolism. Nevertheless, Pctp(-/-) mice exhibit interesting defects in lipid homeostasis, the understanding of which should elucidate the biological functions of PC-TP.

Figure 1

A) Overall structure of human PC-TP. The α-helix identifiers and residue ranges for human PC-TP are α1 (9–22), α2 (64–74), α3 (75–82) and α4 (184–209). The β-strand identifiers and residue ranges are β1 (31–36), β2 (39–46), β3 (51–61), β4 (84–93), β5 (96–104), β6 (111–123), β7 (130–138), β8 (150–162) and β9 (168–178). The Ω-loop identifiers and residue ranges are Ω1 (105–110) and Ω2 (139–149). B) Interactions of PC-TP (blue) with the glycerol-3-phosphorylcholine moiety of 1-palmitoyl,2-linoleoyl-sn-glycerol-3-phosphorylcholine (palmitoyl-linoleoyl phosphatidylcholine) (yellow). The structure of 1,2-dilinoleoyl-sn-glycerol-3-phosphorylcholine (dilinoleoyl phosphatidylcholine) from the PC-TP–phosphatidylcholine complex is superimposed (gray). C) Solvent accessible volume of the binding pocket containing phosphatidylcholine. The phosphatidylcholine molecule occupies approximately 89% of the lipid binding pocket, which extends through two narrow portals 3–5 Å in diameter to bulk solvent. (Reprinted with permission from reference [26]).

Figure 2

The C-terminus of PC-TP is the membrane binding domain. A) The α4 helix of the C-terminus of PC-TP can be subdivided into two functionally distinct types, a membrane spanning helix (α4a) and an amphipathic helix (α4b). B) A model of PC-TP-membrane binding that occurs when α4b aligns at the surface of a bilayer. Extraction of a phosphatidylcholine may be accomplished when α4a penetrates into the membrane.