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Dr Tim Levine
UCL Institute of Ophthalmology
11-43 Bath St
London
EC1V 9EL
Appointment
  • Clinical Lecturer
  • Inst Ophthalmology - Cell Biology
  • Institute of Ophthalmology
  • Faculty of Brain Sciences
Biography


Research Summary

We work on the broad biological question of how lipids and proteins interact inside cells, using budding yeast, a genetically tractable model system. Understanding 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 cardiovascular disease. Many important aspects of intracellular lipid metabolism are conserved between humans and yeast, so that new understanding gained in the single celled organism is highly relevant for eukaryotes in general.


We focus on 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 traditional genetic approach of finding mutants that lack lipid traffic has often failed for membrane contact sites. Instead, we rely on a candidate approach, using bioinformatics tools to predict 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 we named the FFAT motif that we found using PROSITE. This was initially found in proteins that transfer lipids between organelles, but has since been found to be the only way for cytoplasmic proteins to access the endoplasmic reticulum. Binding to VAP allows lipid transfer proteins to form bridges between the endoplasmic reticulum (where most lipids are made) and other organelles to which lipid is transferred. 


From this we moved to discover and study a brand new family of lipid transfer proteins which are anchored at membrane contact sites. We identified this family with the structural bioinformatics tool HHsearch. 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. 


Evolving from our specific use of this tool to make advances in lipid traffic at contact sites, we have made other bioinformatic discoveries, for example identifying the translated product of the C9ORF72 gene as DENN-like. We have bench-marked the likely extent of new prediction and discovery by HHsearch genome-wide. In yeast it may reduce unknown regions by one third (from current level of 15% of ORFs to 10%). To disseminate this knowledge, we have teamed up with the UCL Department of Computer Science to create a S. cerevisiae whole-genome HHsearch database, which will go live in 2017. It will be formatted to be compatible with the Saccharomyces Genome Database (SGD) for publication alongside the current Interpro dataset.


In the future, we will apply high performance structural bioinformatics tools in further ways to enhance accessibility to the cell biology community, and we will use newer, more sensitive tools such as Gremlin Metagenomics.

Teaching Summary

Programme Director: 

Biology of Vision MSc,

This exciting masters course spans the excellent research groups at the world-leading UCL Institute of Ophthalmology. All 40 Principal Investigators are able to offer projects and teach on this course, covering basic cell studies, ground-breaking gene and cell therapies, all the way to the psychophysics of visual perception. In the applied course we have world-leading translational scientists from the Institute who describe the ups, downs, and ways to proceed from bench to bedside.
 

Academic Background
1993 PhD Doctor of Philosophy – Immunology University College London
1986 MBBS Bachelor of Medicine/Bachelor of Surgery – Pathology University College London
1983 BA Bachelor of Arts – Pathology University of Cambridge
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