Dr Tim Levine
We are working on the broad biological question of how lipids and proteins interact inside cells, using the genetically tractable budding yeast Saccharomyces cerevisae model system. Understanding the regulation of lipid metabolism is of great medical importance for diseases prevalent in the Western world, including important ophthalmic diseases (such as Age-related macular degeneration), major brain disorders (Alzheimer's and Parkinson's), and also atherosclerosis and the huge burden of cardiovascular disease. Many important aspects of intracellular lipid metabolism are conserved between humans and yeast, with new understanding gained in the single celled organism being highly relevant for other eukaryotes in general.
The first of our main focus areas is lipid traffic across narrow cytoplasmic gaps where organelles come very close to each other. These membrane contact sites are very poorly understood because they are put together by multiple bridging complexes, and the routes of traffic are circular. Therefore, the usual way to make progress by finding mutants lacking a cellular activity (i.e. genetics) has not worked for membrane contact sites. Instead, we rely on a candidate approach, predicting which proteins are likely to be involved.
Our first major discovery in this field was that VAP, a conserved endoplasmic reticulum protein, binds to a large variety of proteins by picking out a short stretch of primary sequence that we named the FFAT motif. This is most commonly found in proteins that transfer lipids between organelles. The binding of these lipid transfer proteins to VAP allows them to form bridges between the endoplasmic reticulum (where most lipids are made) and other organelles to which lipid is transferred.
We have moved on from this to now study a brand new family of lipid transfer proteins which are anchored at membrane contact sites. We identified this family as key players in lipid biology by applying the state-of-the-art structural bioinformatics tool HHpred. This tool has been highly useful in the lab as a fast and accurate way to identify remote homology between proteins that share almost no identifiable sequence. The tool allows us to find which proteins share the same fold, so are likely to have evolved from a common ancestor.
The second area of interest is the role of phosphoinositide lipids as cellular signposts. After initial work on the binding of pleckstrin homology to phosphoinositides, we have since worked on the oculocerebrorenal syndrome of Lowe (OCRL), a rare and fatal disease that presents with bilateral congenital cataracts, and so has implications for lens epithelial cell biology. By studying OCRL1, the protein mutated in this disease, we hope to generate ideas about treatment that may help the more clinically intractable problems in kidney and brain.
Intracellular Lipid Traffic
The Cell Biology of Eye Disease
Biology of Vision MSc (since 2011)Translational and Regenerative Neuroscience MSc (starts 2014)
Prof Clare Futter; Professor Francesca Cordeiro; Dr Chris Stefan; Prof Karl Matter; Dr Darren Nesbeth; Prof Stephen Moss; Prof Shamshad Cockcroft; Prof Sandip Patel
Prof Anant Menon; Prof Howard Riezman; Prof Christian Ungermann; Prof Susan Henry; Prof Tom Blundell; Dr Nick Ktistakis; Dr Will Prinz; Dr Catherine Tomasetto
- Alpy F, Rousseau A, Schwab Y, Legueux F, Stoll I, Wendling C, Spiegelhalter C, Kessler P, Mathelin C, Rio M-C, Levine TP, Tomasetto C (2013). STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER. JOURNAL OF CELL SCIENCE, 126(23), 5500 - 5512. doi:10.1242/jcs.139295
- Levine TP (2013). A Twoferase for Lipid Transfer at ER-Golgi Contact Sites. DEVELOPMENTAL CELL, 27(4), 369 - 370. doi:10.1016/j.devce1.2013.11.009
- Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ (2013). The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs.. Bioinformatics, 29(4), 499 - 503. doi:10.1093/bioinformatics/bts725
- Chlystun M, Campanella M, Law AL, Duchen MR, Fatimathas L, Levine TP, Gerke V, Moss SE (2013). Regulation of mitochondrial morphogenesis by annexin A6.. PLoS One, 8(1), e53774 - . doi:10.1371/journal.pone.0053774
- Levine TP, Daniels RD, Wong LH, Gatta AT, Gerondopoulos A, Barr FA (2013). Discovery of new Longin and Roadblock domains that form platforms for small GTPases in Ragulator and TRAPP-II.. Small GTPases, 4(2), 62 - 69. doi:10.4161/sgtp.24262
- Levine TP, Menon AK (2013). A protein pair with PIPs inside.. Structure, 21(7), 1070 - 1071. doi:10.1016/j.str.2013.06.010
- Levine TP (2013). A twoferase for lipid transfer at ER-golgi contact sites.. Dev Cell, 27(4), 369 - 370. doi:10.1016/j.devcel.2013.11.009
- Mikitova V, Levine TP (2012). Analysis of the key elements of FFAT-like motifs identifies new proteins that potentially bind VAP on the ER, including two AKAPs and FAPP2.. PLoS One, 7(1), e30455 - . doi:10.1371/journal.pone.0030455
- Levine TP (2011). Lipid traffic: Osh4p makes an unexpected exchange.. J Cell Biol, 195(6), 927 - 929. doi:10.1083/jcb.201111074
- Hayes MJ, Bryon K, Satkurunathan J, LEVINE TP (2011). Yeast homologues of three BLOC 1 subunits highlight KxDL proteins as conserved interactors of BLOC-1. Traffic, 12(3), 260 - 268.
- Grieve AG, Daniels RD, Sanchez-Heras E, Hayes MJ, Moss SE, Matter K, Lowe M, Levine TP (2011). Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.. PLoS One, 6(8), e24044 - . doi:10.1371/journal.pone.0024044
- Hayes MJ, Shao DM, Grieve A, Levine T, Bailly M, Moss SE (2009). Annexin A2 at the interface between F-actin and membranes enriched in phosphatidylinositol 4,5,-bisphosphate. Biochim.Biophys.Acta, 1793(6), 1086 - 1095.
- Suzuki H, Kanekura K, Levine TP, Kohno K, Olkkonen VM, Aiso S, Matsuoka M (2009). ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-related death by inducing aggregation of co-expressed wild-type VAPB. J.Neurochem., 108(4), 973 - 985.
- Hayes MJ, Shao DM, Grieve A, Levine T, Bailly M, Moss SE (2008). Annexin A2 at the interface between F-actin and membranes enriched in phosphatidylinositol 4,5,-bisphosphate. Biochim.Biophys.Acta, , - .
- Levine TP (2007). A lipid transfer protein that transfers lipid. J.Cell Biol., 179(1), 11 - 13.
- Loewen CJR, Young BP, Tavassoli S, Levine TP (2007). Inheritance of cortical ER in yeast is required for normal septin organisation. The Journal of Cell Biology, 179(3), 467 - 483. doi:10.1083/jcb.200708205
- Loewen CJR, Levine TP (2006). Inter-organelle membrane contact sites: through a glass, darkly.. Curr Opin Cell Biol., 18, 371 - 378.
- Yeung T, Terebiznik M, Yu L, Silvius J, Abidi WM, Philips M, Levine T, Kapus A, Grinstein S (2006). Receptor activation alters inner surface potential during phagocytosis.. Science, 313(5785), 347 - 351. doi:10.1126/science.1129551
- Levine T (2005). A new way for sterols to walk on water. MOL CELL, 19(6), 722 - 723.
- Holthuis JC, Levine TP (2005). Lipid traffic: floppy drives and a superhighway. NAT REV MOL CELL BIOL, 6(3), 209 - 220.
- Loewen CJ, Levine TP (2005). A highly conserved binding site in vesicle-associated membrane protein-associated protein (VAP) for the FFAT motif of lipid-binding proteins. J BIOL CHEM, 280(14), 14097 - 14104.
- Loewen CJ, Levine TP (2005). A highly conserved binding site in VAP for the FFAT motif of lipid binding proteins.. Journal of Biological Chemistry, 280, 14097 - 14104. doi:10.1074/jbc.M500147200
- Levine T, Rabouille C (2005). Endoplasmic reticulum: one continuous network compartmentalized by extrinsic cues. CURR OPIN CELL BIOL, 17(4), 362 - 368.
- Levine T (2004). Short-range intracellular trafficking of small molecules across endoplasmic reticulum junctions.. Trends in cell biology, 14(9), 483 - 490. doi:10.1016/j.tcb.2004.07.017
- Roy A, Levine TP (2004). Multiple pools of phosphatidylinositol 4-phosphate detected using the pleckstrin homology domain of Osh2p.. Journal of Biological Chemistry, 279(43), 44683 - 44689. doi:10.1074/jbc.M401583200
- Levine T (2004). SSD: sterol-sensing direct.. Developmental Cell, 7(2), 152 - 153.
- Loewen CJ, Gaspar ML, Jesch SA, Delon C, Ktistakis NT, Henry SA, Levine TP (2004). Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid.. Science, 304(5677), 1644 - 1647. doi:10.1126/science.1096083
- Olkkonen VM, Levine TP (2004). Oxysterol binding proteins: in more than one place at one time?. Biochemistry and Cell Biology, 82(1), 87 - 98.
- Hayes MJ, Merrifield CJ, Shao D, Ayala-Sanmartin J, Schorey CD, Levine TP, Proust J, Curran J, Bailly M, Moss SE (2004). Annexin 2 binding to phosphatidylinositol 4,5-bisphosphate on endocytic vesicles is regulated by the stress response pathway.. Journal of Biological Chemistry, 279(14), 14157 - 14164.
- Loewen CJ, Roy A, Levine TP (2003). A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. The EMBO Journal, 22(9), 2025 - 2035. doi:10.1093/emboj/cdg201
- Levine TP, Munro S (2002). Targeting of Golgi-specific pleckstrin homology domains involves both PtdIns 4-kinase-dependent and -independent components. Current Biology, 12(9), 695 - 704.
- Loewen CJ, Levine TP (2002). Cholesterol Homeostasis: Not until the SCAP Lady INSIGs. Current Biology, 12(22), R779 - R781. doi:10.1016/S0960-9822(02)01292-7
- Levine TP, Munro S (2001). Dual targeting of Osh1p, a yeast homologue of oxysterol-binding protein, to both the Golgi and the nucleus-vacuole junction. Molecular Biology of the Cell, 12(6), 1633 - 1644.
- (2000). Inositol phosphorylceramide synthase is located in the Golgi apparatus of Saccharomyces cerevisiae. Molecular Biology of the Cell, 11(7), 2267 - 2281.
- Levine TP, Chain BM (1993). Endocytic activity of dendritic cells is similar to other antigen presenting cells.. Adv Exp Med Biol, 329, 11 - 15.
- Levine TP, Chain BM (1992). Endocytosis by antigen presenting cells: dendritic cells are as endocytically active as other antigen presenting cells.. Proc Natl Acad Sci U S A, 89(17), 8342 - 8346.
- Levine TP, Chain BM (1991). The cell biology of antigen processing.. Crit Rev Biochem Mol Biol, 26(5-6), 439 - 473. doi:10.3109/10409239109086790
- Roy AAL, T (). Reconstitution of a membrane contact site with one protein: Osh1 at the nucleus vacuole junction. , , - .