Introduction

Research Groups

Select Research Group Head Prof. Sir Tom Blundell Prof. Kevin Brindle Dr Bill Broadhurst Dr Guy Brown Dr Mark Carrington Prof. Paul Dupree Prof. Gerard Evan - Head of Dept Prof. Richard Farndale Dr Giorgio Favrin Dr Jenny Gallop Dr Nick Gay Dr Andrew Grace Dr Jules Griffin Dr Brian Hendrich Dr Andrew Hesketh Dr Robin Hesketh Dr Matt Higgins Dr Florian Hollfelder Dr Hee-Jeon Hong Prof. Chris Howe Dr Marko Hyvonen Prof. Steve Jackson Dr Tony Jackson Prof. Richard Jackson Prof. Ernest Laue Prof. Peter Leadlay Dr Kathryn Lilley Dr Karen Lipkow Dr Rick Livesey Prof. Ben Luisi Dr Sarah Lummis Dr Juan Mata Dr John McCafferty Prof. Jim Metcalfe Dr Masanori Mishima Dr Eric Miska Dr Tom Monie Dr Helen Mott Dr Natasha Murzina Dr Daniel Nietlispach Dr Darerca Owen Prof. Steve Oliver Dr Luca Pellegrini Dr Markus Ralser Dr Nick Robinson Prof. George Salmond Dr Deirdre Scadden Dr José Silva Prof. Austin Smith Prof. Chris Smith Dr Nancy Standart Prof. Dame Jean Thomas Dr Aviva Tolkovsky Dr Martin Welch Dr Joyce Wong Dr Nianshu Zhang

Service & Research Support Facilities

Select by Subject or Manager DNA Sequencing Facility . . . . . Mr John Lester _______________________________ Quantitative Proteomics . . . . . Dr Kathryn Lilley _______________________________ Proteomics Core Services . . . . . Dr Mike Deery _______________________________ Protein & Nucleic Acid Chemistry . . . . . Dr Len Packman _______________________________ Metabolomics . . . . . Dr Jules Griffin _______________________________ Baculovirus Facility . . . . . Dr Darerca Owen _______________________________ Biophysics Facility . . . . . Dr Katherine Stott _______________________________ Crystallographic X-ray Facility . . . . . Dr Dima Chirgadze _______________________________ NMR spectroscopy . . . . . Dr Daniel Nietlispach _______________________________ Fermentation Facility . . . . . Dr Nianshu Zhang _______________________________ Bioinformatics & Computational Biology Services . . . . . Dr Jenny Barna _______________________________ Computer & IT Support . . . . . Dr Erik Timmers _______________________________

Past members last known active weblink

Select past member of Department Dr Stephen Bell Prof. Jonathan Blackburn Dr David Brown Dr Pak-Lee Chau Dr Hal Dixon (deceased) Dr Jessica Downs Prof. David Ellar Dr Paul Kemp Dr Simon Lovell Dr Kenji Mizuguchi Dr Massimo Paoli Prof. Richard Perham Dr Peter Reynolds Dr Philip Rubery Dr Gerry Smith Dr Margaret Sunde Prof. Jamie Vandenberg Dr Kira Weissman

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Molecular Cell Biology of Trypanosomes

Research Groupings: Infection and Immunity | Structural and molecular cell biology

As well as being causal agents of disease, trypanosmes diverged at an early stage of the eukaryotic lineage and offer the opportunty to investigate molecular processes that are different to other eukaryotes. Over the past twenty years they have been developed as a model experimental system and have been central to the elucidation of several basic molecular processes common to all eukaryotes such as GPI-anchoring of cell surface proteins and trans splicing of mRNA. Trypanosomes are amenable to interrogation with the complete range of molecular biology techniques and the recent completion of the genome sequences of five trypanomastids will facilitate rapid advances in our understanding of these organisms in the next few years. Two unique features of trypanosome biology are investigated in the lab.

Trypanosomes expressing a plasma membrane localized green fluorescent protein. Reporter strains expressing GFP regulated by the 3’UTR of a developmentally regaled gene will be used to screen whole genome RNAi libraries.

The organisation and function of cell surface proteins on the bloodstream form.
The cell surface is covered with a monolayer of a single protein, the VSG that functions at two levels, first by undergoing antigenic variation it permits a trypanosome population to persist in the host; second, it forms a physical barrier to protect underlying invariant cell surface proteins, such as ISGs, from the molecular effectors of the host’s immune system. We are aiming to produce a dynamic model of the VSG monolayer, using the known dimensions of the VSG and the most accurate values for the density of VSG dimers on the cell surface, that will allow testable predictions such as the degree of penetration by molecules of various sizes.

Currently, only the structure of the N-terminal domain of the VSG is known and toward the goal of producing a model, we have just solved the structure of the VSG C-terminal domain. In order to integrate the ISGs into this model we are aiming to solve the structure of one of the ISG family members and also to determine the function of several ISGs. This has been addressed through the generation of tetracycline inducible RNA interference lines that are able to ablate ISG expression. The phenotypes of these cell lines is currently being determined.

The mechanism of developmentally regulated mRNA stability.
Transcription of protein coding genes in trypanosomes is unusual, arrays of genes are constitutively transcribed as polycistrons and individual monocistronic mRNAs processed from the pre-RNA. Thus, regulation of gene expression is post-transcriptional. Developmentally regulated gene expression is achieved through instability of individual mRNAs in one life cycle stage but not another. To determine the mechanism of this instability, transgenic cell lines containing mutated versions of the genes are analysed to determine whether developmental regulation is lost. As a second line of approach to the problem, we have used the genome sequence to isolate orthologues of most of the components of the mRNA turnover pathway. The function of these genes is being tested by using inducible RNAi to ablate expression of target genes and assaying the steady state levels of normally unstable mRNAs.

Lab members
Susanne Kramer, Flora Logan, Angela Schwede, Jack D Sunter, Helena Webb, Giles Velarde

References