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First published online June 23, 2005
doi: 10.1242/10.1242/jcs.02485

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Give lipids a START: the StAR-related lipid transfer (START) domain in mammals

¹ Inserm, U682 Strasbourg, F67200, Development and Physiopathology of the Intestine and Pancreas, University Louis Pasteur, Strasbourg, France
² Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Pathologie Moléculaire, UPR 6520 CNRS/U596 INSERM, Université Louis Pasteur, BP10142, 67404 Illkirch, C.U. de Strasbourg, France

View larger version (37K): [in a new window]   Fig. 1. Phylogenetic tree and domain organizations of the 15 START-domain proteins in humans. START domain sequences were aligned by the Eclustalw program (Genetics Computer Group, Madison, WI). The phylogenetic tree was drawn with the drawtree software [J. Felsenstein, 1993, PHYLIP (Phylogeny Inference Package) v.3.5c, Department of Genome Sciences, University of Washington, Seattle, WA]. Abbreviations: Mt, mitochondrial targeting motif; MENTAL, MLN64 N-terminal domain; PH, pleckstrin homology domain; FFAT, two phenylalanines in an acidic tract motif responsible for ER targeting; RHOGAP, Rho-GTPase-activating-protein domain; SAM, sterile alpha motif; THIO, acyl-CoA thioesterase domain.

View larger version (44K): [in a new window]   Fig. 2. Structure of the START domains of MLN64 (A) and PCTP with its ligand (B). (A) Ribbon diagram of the START domain of MLN64 (PDB ID code: 1EM2). Secondary structural elements and the C- and N-termini are labeled. MLN64 has a central ß-sheet (yellow) gripped by N-terminal (1) and C-terminal (4) -helices (red), the latter being closely packed above the curved sheet. (B). Cut-away view of the molecular surface of the START domain of PCTP complexed with a phosphatidylcholine molecule (DLPC, dilinoleoyl-sn-glycerol-3-phosphorylcholine) (PDB ID code: 1LN1). The DLPC molecule (shown in stick representation) is located in the hydrophobic tunnel formed in the START domain. The orientation of the START domain is similar to that in A. The protein surface is colored according to secondary structure: red for helices, yellow for ß strands and green for loops. These figures were prepared with PyMOL software (W. L. DeLano, 2002, The PyMOL molecular graphics system. http://www.pymol.org).

View larger version (48K): [in a new window]   Fig. 3. START-containing proteins have distinct subcellular localization. (A) Cotransfection of HeLa cells with StAR (green) and MLN64 (red). MLN64 and StAR show a vesicular staining pattern corresponding to endosomes and mitochondria, respectively. (B) Cotransfection of HeLa cells with MLN64 (red) and GFP-STARD4 (green). MLN64 shows a typical punctate staining corresponding to endosomes whereas the GFP-STARD4 fusion protein gives a diffuse nuclear and cytoplasmic signal. Nuclei were counterstained with Hoechst-33258 dye.

View larger version (42K): [in a new window]   Fig. 4. Conveying lipids across the cytoplasm. (A) Mode of action of a START-only protein. In its unliganded form, the START domain interacts with the membrane through its C-terminal 4 helix. This interaction induces a conformational change and opens the lipid-binding pocket. When the lipid (yellow) is occupying the pocket, the protein conformation changes again and the lid is closed. The liganded form of the START protein must be targeted to an acceptor membrane to deliver its lipid. (B) Mode of action of MLN64. The MENTAL domain of MLN64 (blue) anchors it to endosome membranes, leaving its C-terminal START domain (green) in the cytoplasm. The START domain of MLN64 might work by extracting cholesterol (yellow) bound to its MENTAL domain from the late endosome membrane and transfer it to a closely positioned acceptor membrane. This model would allow significant and rapid cholesterol transfer.

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