StAR-related Lipid Transfer (START) Proteins: Mediators of Intracellular Lipid Metabolism

Abstract

StAR-related lipid transfer (START) domains are 210-amino acid lipid binding domains implicated in intracellular lipid transport, lipid metabolism, and cell signaling events. The prototype is the steroidogenic acute regulatory protein (StAR), which transfers cholesterol to mitochondria in steroid hormone-producing cells (1). START domains are found in an extensive protein family, including START domain only and multidomain proteins, but lipid ligands have only been identified in a few cases (2). The human and mouse genomes each have 15 genes encoding START domains (Table I), and phylogenetic analysis divides the family into six subfamilies (Fig. 1, A and B) (3). X-ray crystal structures have been solved for the MLN64 START domain (4), StarD4 (5), and phosphatidylcholine transfer protein (PCTP) (6). All three share the same helix-grip fold (7), with -helices at the N and C termini separated by nine -strands and two shorter -helices. The curved -sheet forms a deep pocket with the C-terminal -helix acting as a lid, resulting in an internal hydrophobic cavity (Fig. 2). The START structure differs from other hydrophobic cavity lipid-binding proteins, such as sterol carrier protein 2 (SCP-2) (8), phosphatidylinositol transfer protein (PITP) (9), and the fatty acid-binding proteins (FABPs) (10). The PCTP structure was reported with a phosphatidylcholine (PC) molecule in the cavity (6), whereas the MLN64 and StarD4 structures contain cavities large enough ( 850 A) to accommodate a cholesterol ligand ( 740 A) (5). In each structure, lipid entry or egress would require a major conformational change, most likely opening or unfolding of the C-terminal -helix lid. In fact, this helix of PCTP has been implicated in membrane binding and PC extraction (11). Furthermore, StAR can form partially unfolded states (12) and loses helical content upon binding a cholesterol analogue (13). Recent modeling of StAR using structure-based thermodynamics showed that an open lid conformational state can exist at equilibrium and that cholesterol binding and lid closure would significantly stabilize the complex (14).