Comparative Structural Analysis of Lipid Binding START Domains

Abstract

BackgroundSteroidogenic acute regulatory (StAR) protein related lipid transfer (START) domains are small globular modules that form a cavity where lipids and lipid hormones bind. These domains can transport ligands to facilitate lipid exchange between biological membranes, and they have been postulated to modulate the activity of other domains of the protein in response to ligand binding. More than a dozen human genes encode START domains, and several of them are implicated in a disease.Principal FindingsWe report crystal structures of the human STARD1, STARD5, STARD13 and STARD14 lipid transfer domains. These represent four of the six functional classes of START domains.SignificanceSequence alignments based on these and previously reported crystal structures define the structural determinants of human START domains, both those related to structural framework and those involved in ligand specificity.Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

The mammalian START domain protein family in lipid transport in health and disease

“…The carboxyl-terminal a helix is proposed to serve as a 'cap' to the ligand-binding site, with lipid access to the binding pocket requiring a conformational change in the START domain and movement of the C-terminal helix , Bose et al 2008a. To date, crystal structures for the START domains of hSTARD1, hSTARD5, hSTARD2/PCTP, STARD11/CERT, hSTARD13, and hSTARD14 have been reported and the data confirm the basic threedimensional helix-grip fold structure across the five mammalian subfamilies that defines this family of proteins (Roderick et al 2002, Kudo et al 2008, 2010, Thorsell et al 2011. Modeling of START domain conformational changes and mechanisms for cholesterol absorption/desorption have been reviewed elsewhere , Miller 2007, Lavigne et al 2010.…”

“…The crystal structure for the START domain of STARD14/ACOT11_v2/BFIT2 shows that the functionally critical C-terminal a helix is broken into two shorter helices (Thorsell et al 2011). Electron density consistent with a fatty acid filled the ligand-binding cavity in the crystal, but the actual ligand and whether it is a fatty acid was not solved.…”

“…In liver mitochondria, cholesterol is hydroxylated on the side chain at position C27 or C25 by the cytochrome P450 enzyme CYP27A1 to produce the oxysterols 27-hydroxycholesterol (27HC) or 25-hydroxycholesterol (25HC) (Li et al 2007). In addition to simply serving as intermediates in bile acid biosynthetic pathway, 27HC and 25HC are cellular signals (Tsujishita & Hurley 2000, Roderick et al 2002, Olayioye et al 2005, Murcia et al 2006, Bose et al 2008a,b, Kudo et al 2008, Rodriguez-Agudo et al 2008, Barbar et al 2009, Horibata & Sugimoto 2010, Thorsell et al 2011 (Kirkby et al 2010).…”

“…New data on the crystal structure for STARD13/DLC-2, however, indicate that the STARD13/DLC-2 ligand-binding pocket is smaller and contains polar residues that make it different from the cholesterol and phospholipid START proteins. The authors propose that a charged lipid would be a likely binding candidate (Thorsell et al 2011). Once the START domain ligands have been defined, this information will help to elucidate the biological significance for the START domain within this family of RhoGAP proteins.…”

The regulation of rhoA by stard 13 in focal adhesions is essential for astrocytoma cell motility. (c2013)

“…StarD13 consists of an Nterminal SAM motif and a C-terminal START domain. In addition, it contains a RhoGAP domain, which is important to its function (Ching, et al, 2003;Thorsell, et al, 2011;Ullmannova & Popescu, 2006 …”