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Results

Conference on drug development for the third world. 22 May 2006

Conference on Drug Development for the Third World The challenge of quantitatively predicting the biological potency of new drugs based on computational physics tools is not so far from being met. Unfortunately, however, little attention has been paid to the computer-aided design of drugs in areas where pharmaceutical companies have little incentive for significant investment. To involve computational (bio) physicists from developing countries in topics related to drug design, the Abdus Salam International Centre for Theoretical Physics (ICTP), Trieste will organise a Conference on Drug Development for the Third World, to take place from 5 to 9 June 2006. The Conference will present both computational and experimental approaches to therapies, with applications to specific disorders or systems. The lectures will be complemented by practical sessions on bioinformatics and molecular docking. Topics will include: 1) Computer-aided drug design 2) Molecular simulations of drug/target complexes 3) Parasitic diseases 4) Target for anti-AIDS therapy 5) Medicinal chemistry of malaria 6) Vaccine development Scientists and students from all countries that are members of the United Nations, UNESCO or IAEA may attend the Conference. Although the main purpose of the ICTP is to help researchers from developing nations through a programme of training activities within a framework of international cooperation, students and post-doctoral scientists from developed countries are also welcome to attend. The Conference will be conducted in English.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University of Dundee

The 11th World Congress of the World Federation of Public Health Association "Public Health in a Globalized World: Breaking Down Political, Social, and Economic Barriers." 26 Apr 2006

Title of meeting: The 11th World Congress of the World Federation of Public Health Association in conjunction with the 8th Brazilian Congress of Collective Health entitled, Public Health in a Globalized World: Breaking Down Political, Social, and Economic Barriers.

Lifecourse, wellbeing and public policy in developing countries 22 May 2006

Life course, wellbeing and public policy in developing countries There is a need to develop new frameworks which facilitate analysis of demographic and epidemiological change in developing countries. No substantial research, publication or meeting has sought to explore the potential of life course frameworks to this end. Bringing together academics from a range of discipline and backgrounds, this conference will provide a platform for a significant shift in understandings of wellbeing and health in developing countries. The conference will be divided into four sessions. The first of these will explore different approaches to conceptualising the life course and will consider their specific applications to developing countries. Different speakers will explore life course from clinical, sociological, anthropological and demographic perspectives. The second session will focus on aspects of life course which relate to fertility, reproduction and demographic change in developing countries. The third session will consider how life course frameworks can enhance our understanding of issues relating to health and wellbeing in developing countries, and will pay particular attention to policy implications. The meeting will conclude with a roundtable and a discussion of research and publication plans. It is planned that the workshop will lead on to an academic network on life course, health and wellbeing in developing countries, which will take the form of an electronic discussion forum as well as future meetings and projects.

Amount: £3,000
Funder: The Wellcome Trust
Recipient: University of East Anglia

Gordon conference on macromolecular organisation and cell function: cellular systems biology. 12 Jun 2006

The Gordon Research Conference has been meeting biannually since 1987, with the first conference organized by Paul A. Srere and Mary Ellen Jones. The conference was held five times in the winter, at sites in California, with the original title of "Enzyme Organization and Cell Function." Because of rapidly developing and widespread interest in the occurrence and importance of the intracellular organization of macromolecules and other enzymes, the title was changed to Macromolecular Organization and Cell Function by a vote of the participants in the 1995 conference. The mission of the Gordon Research Conferences is to address developments "at the frontiers of science", and the scientific program and participants are required to fulfil this mission. The organizers of the 2006 meeting are committed to maintaining the high scientific standards set by the previous conference chairs while enhancing attendance of junior scientists through acquisition of significant funds to offset their expenses. The program will continue to focus on the most recent advances in the field of cellular organization, introduce directions for the future, and promote general discussion, with the goal of providing a stimulating and valuable experience for all of the conferees. A unique aspect of this conference is that it addresses a special need within the growing community of scientists focusing their attention on cellular organization and biocomplexity. It does this by cutting across disciplines to bring together individuals with different areas of expertise who are addressing diverse, yet overlapping, scientific questions and goals. The conference is exceptional in promoting the interaction of people at all levels of experience and background, both because a significant number of the conferees have not attended previously, and also because the conference is organized to promote both formal and informal discussions.

Amount: £5,717
Funder: The Wellcome Trust
Recipient: University of Manchester

The future of A level science - a series of stakeholder conferences aimed at informing practice and policy. 30 Aug 2006

We intend to set up a programme of stakeholder conferences to inform the new Physics, Chemistry, Biology and Psychology A level courses due to be introduced in 2008. The National Science Learning Centre will host four events leading to the publication of a report informing practice and policy, and implementation of the new courses. We anticipate that 240 key education, science and other stakeholders will be involved in the programme directly, and that the outcomes and outputs will affect many thousands over the subsequent years. This systematic approach is long overdue and would help to ensure that the content and approach at A Level better meets the needs of science, the FE and schools sector, young people and industry. The Qualifications and Curriculum Authority has expressed enthusiastic interest in this model and were it to be successful, we would expect it to be adopted more widely as mechanism for informing curriculum development in science and beyond. The Stakeholder Conference Programme will achieve the following objectives: To identify priorities, themes, core issues and contexts for each of the four science A levels, amongst each of the stakeholder groups; To develop a methodology to inform curriculum development that could be replicated and extended; To act as a forum where research scientists can work with science educationalists to illustrate curriculum content with contemporary examples; To professionalise and make more transparent the curriculum development process. Main audience: 1. Conference attendees and the organisations they represent. 2. Post-16 lecturers and teachers. 3. Policymakers.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of York

Public enemy No 1 or your new best friend? An exhibition and series of public lectures exploring the fascintating relationships between people and the parasites that live inside us. 28 Mar 2006

Public enemy No. 1 or your new best friend? An exhibition and series of public lectures exploring the fascinating relationships between people and the parasites that live inside us The main objective of this project is to communicate the fascinating relationships between people and their parasites. The development of accessible exhibits, utilising large scale portable pop-up display structures, along with a series of public lectures will illustrate and discuss different consequences of our various interactions with parasites. Our encounters with parasites can sometimes be very dangerous resulting in life-threatening diseases such as malaria which is still responsible for the deaths of over 2000 African children every day. Alternatively, recent research in understanding how parasitic worms can manipulate our immune systems may offer new solutions in the treatment of diseases such as asthma, diabetes or Crohn's disease. The discovery of the cause of many important parasitic diseases owes much to pioneering Scottish scientists and explorers; their inspirational stories will be illustrated using a series of banner sized posters, along with graphic descriptions of the problems caused by several key parasites to this day. The project aims to engage and inform the public by presenting a historical perspective alongside new advances in biomedical research in an entertaining and accessible manner which will be aimed at the non-expert and hopefully will appeal to older children and adults. The public lectures will offer an opportunity for members of the public and scientists to engage in discussion and debate. It is planned to launch the project in Glasgow to coincide with the 11th International Congress of Parasitology, August 2006 and thereafter to take the exhibition and organise public lectures at other venues initially in Scotland and then to other locations in the UK.

Amount: £29,198
Funder: The Wellcome Trust
Recipient: Moredun Research Inst Edinburgh

Visualising human health and medicine throughout history using transformational make-up techniques. 26 Apr 2006

VISUALISING HUMAN HEALTH AND MEDICINE THROUGHOUT HISTORY USING TRANSFORMATIONAL MAKE-UP TECHNIQUES 1. The Centre for the History of Medicine is currently expanding its outreach work with a new project. The main aim is to bring the history of medicine to life through the medium of 'special effects' make-up. In this way audiences can explore and assume the physical and emotional characteristics associated with trauma and disease. This particular approach very literally animates and demonstrates the characteristics surrounding disease and health while providing participants with the chance to interpret and visualise the effects of a particular ailment using a combination of both artistic and scientific skills using a three-dimensional approach. In this way injuries, for example war wounds, and diseases such as smallpox and scarlet fever, will be realistically represented and each subject grounded in its appropriate medical-historical context. 2. The above method will be delivered in a series of practical demonstration sessions in schools, FE and sixth form colleges, museums and galleries, with supporting exercises and worksheets written on agreed topics. The project hopes to bring to teachers, pupils, parents and the wider community a better understanding of medical history for those with little or no knowledge of the subject. 3. By using this technique as the means of communicating health, disease and society, a variety of processes are used in the craft of special effects make-up, including knowledge of a number of affiliated subjects, including anatomy, chemistry, sculpture and history of art. 4. The principal applicant is trained to the standards of the International Health and Beauty Council of Great Britain, holds a BA in the History of Art and Design and is currently studying for an MPhil degree undertaking research into the toxicology of cosmetics and body ornamentation in the ancient world for which the applicant holds a Centre Bursary.

Amount: £7,005
Funder: The Wellcome Trust
Recipient: University of Birmingham

Designs for Life. 31 Dec 2005

'Designs for Life' Exploring the visualisation of developments in genetic research through analysis of a series of controlled production collaborations and integrated public engagement. Genetic scientists have often indicated difficulty in presenting and interpreting their research to an extended scientific community and the wider public. As developments in science and technology progress at an ever-increasing rate it is essential to understand how new knowledge is to be visually interpreted and communicated. This problem has particular significance at a time when public debate and anxiety is widespread around issues raised by gene and cell research. The proposed activity is based upon the potential of visual art to communicate often complex ideas to a general audience. Effective ways by which this expertise can be used to mediate between the scientific specialist and a wider community will be explored. Debate will be initiated around methodologies in the processing of visual information in a scientific context. It will harness expertise within the Biomedical Research Centre and the Visual Research Centre at the University of Dundee. This will be achieved through a series of publicly accessible collaborations between the artist Paul Harrison and twelve individual scientists working in specific yet related areas of cell research. The research will establish productive methodologies for collaboration, tested through public exhibition of visual outcomes, debated in an academic symposium and disseminated through a dedicated website and publication. The aim of the project is to bring together a spectrum audience including scientists, artists, academics, students, general public/visitors to DCA and school and community groups, located primarily, but by no means exclusively, in the environs of Dundee.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of Dundee

How gay are your genes? 23 Jan 2006

How gay are your genes? "How gay is your genes?" is a science engagement project working with lesbian, gay and bisexual community in North East England, with the aim of promoting awareness and debate about the life sciences. Phase one commenced in 2004, with Lisa Matthews holding workshops and giving talks about genetics to gay community groups, and has been funded by COPUS. More than 300 individuals have participated to date in discussions of science, genetic research in general, and claims about genetic factors in sexual orientation in particular. We believe that this is the first science engagement project targeted at lesbian, gay and bisexual people. Phase two will commence in Autumn 2005, and will involve deeper work with a smaller group of lesbian and gay people, giving them the opportunity to hear from visiting speakers - for example, Professor Nancy Roughgarden, Professor Jenny Kitzinger, Dr Su Stenhouse - and to develop creative writing responses to genetics. The current People award application, will add a visual arts element to this innovative outreach project. Predrag Pajdic, a contemporary video artist, who is gay and has a gay identical twin, will work with Lisa Matthews and the gay community participants to develop artwork reflecting the responses and concerns which gay people have expressed about genetic research on sexuality. Pajdic's artwork will be exhibited in Newcastle's Hatton Gallery, alongside creative writing produced during the outreach workshops, to a broad audience - general public as well as gay community. Versions of the artworks and supporting material will also be available to a global audience via a website.

Amount: £20,700
Funder: The Wellcome Trust
Recipient: Newcastle University

Designs for life: an art/science collaboration to produce a quilted artpiece representing debate around contemporary biomedical science. 19 Oct 2005

We will make a giant fabric-based quilt that represents the ideas, concerns and issues of group of women about the biosciences relating to the Diamond Light Source, a synchrotron research facility. Groups from the Women's Institute will work with scientists and artists to design and construct pieces of artwork in response to discussion and debate about the study of diseases, drug development and environmental health. By providing suitable templates for the individual pieces of artwork - specifying size, shape and weight - we will assemble the pieces made by the participating groups into a final quilt-like structure. The quilt will be approximately 4m x 7m in size and will consist of various fabrics of contrasting texture and colour, providing significant visual impact. The quilt will then be displayed, over a three-month period, in various public places such as shopping centres, museums and leisure centres, facilitating ongoing discussion among a wide range of the viewing public. Accompanying explanatory notes and images will also be made available and feedback from the public will be encouraged. After the initial display run the quilt will be housed in the atrium at Diamond Light Source allowing continuing visibility to the visiting public, business community and scientists.

Amount: £28,950
Funder: The Wellcome Trust
Recipient: The Oxford Trust

History of development of current ideas about disease specific action of psychiatric drugs. 14 Jun 2006

In this research I will look at the history of psychopharmacology to investigate the development of the idea that psychiatric drugs are disease specific treatments. In my psychiatric research I have suggested that there is little evidence for this model of drug action. I suggested that an alternative view of drugs as inducing abnormal states that may occasionally be useful in psychiatric conditions is more consistent with available evidence. Prior to the 1950s drugs were not generally believed to act on the physical basis of disease. Drugs were seen as creating drug induced effects such as sedation, that could be useful in the context of mental hospital care. During the 1950s and 1960s a new generation of drugs were introduced into psychiatry, which gradually came to be seen as acting directly on the physical basis of diseases or symptoms. I am interested in exploring how and why this change of view came about. In particular I am interested in whether professional and commercial interests influenced the changing notions of drug action during this period. To explore the change of view about drug action I will look at the examples of the antipsychotic or neuroleptic drugs and the antidepressants. I will try and establish when antipsychotic drugs and antidepressants came to be seen as disease specific treatments. I have previously investigated how notions of specificity had emerged in relation to the physical treatments in the 1940s. I will look for evidence of whether views about physical treatment methods influenced the adoption of disease specific models of the action of neuroleptic drugs and antidepressants. I will explore how the concurrent interests of the psychiatric profession and the pharmaceutical industry may have influenced the development and adoption of this model of drug action.

Control and the therapeutic trial in 20th century Britain. 09 Mar 2006

I propose to undertake further research into the subject of my MD thesis 'Control and the therapeutic trial 1918 - 1948', awarded earlier this year, in order to publish the work as a book. My thesis offered a novel assessment of the genesis and hegemony of today's 'controlled trial' though an historical analysis of the rhetorical associations of the term 'controlled' and their exploitation, in particular, by the Medical Research Council (MRC.) My analysis has considerable implications for current medical research and evidence-based practice. Although I briefly discussed these implications in my thesis, I intend to expand this analysis, including an overview of the use of the rhetoric of the 'controlled trial' from 1948 to the end of the 20th century (outside the scope of my original thesis) and further discussion of the extent to which its rhetorical function is implicit in current research and lay discourse. This would involve analysis of medical journals and textbooks, lay newspapers and magazines covering the latter half of the twentieth century, together with further reading of secondary sources which largely fell outside my original thesis. I also intend to explore further, notions of 'control' during the earlier twentieth century.

Amount: £32,050
Funder: The Wellcome Trust
Recipient: University College London

To Formulate a Plan for Better Living: Paul Rotha and the Definition of Scientific Documentary. 10 Nov 2005

My goal is to complete the research and to write up for publication as a book, under the working title To Formulate a Plan For Better Living: Paul Rotha and the Definition of Scientific Documentary, which draws on my work on the scientific documentary form that flourished in the mid 20th century with a stress on public health measures as the epitome of a socially engaged model of science. Key new research includes: Research from primary sources on the origins of scientific filmmaking in Britain up to 1939. Research the model of technological modernism conveyed especially in the films of the GPO Film Unit. Finalise research on the representation of nutrition from late 1936 through to 1939 and, via personal papers, study of relations between scientists in the 'social relations of science' movement and documentary filmmakers. Research the evolution of debates about planning, reconstruction, nutrition and their representation, May 1943 to May 1945. Survey scientific and medical documentary films 1945-1951 to confirm my working assumptions; pursue the relations of the broader groups of participants. Research Rotha's period at the BBC and the relevant films made there.

Amount: £62,509
Funder: The Wellcome Trust
Recipient: Science Museum

Milk: Pure or Poisonous? The History of a Key Food and its Health Consequences, 1850-1960. 10 Nov 2005

My goal is to write an innovative book that will use a single commodity as an anchor point for a study of the interactions between food supplies, health and politics. In contemporary food chains, the separation of the places of production and consumption under the conditions of modernity was founded upon trust in anonymous intermediaries. This trust was fragile and was increasingly mediated by expert knowledge of commodity control. Two challenges were particularly apparent. First, there was the threat of adulteration, which in the case of milk was an ever-present problem up to the 1920s; second, the spread of diseases such as tuberculosis through infected milk and meat was established to be a hazard. In consequence, there was a priority in negotiating conventions that would encourage trade while minimizing risk to the consumer of being cheated or infected. I will chart the origins and endurance of these conventions. The quality-checking systems were conceived from network-shaping series of social practices, standardized measuring instruments, and analytical procedures. In my view, it is impossible to grasp the present day 'quality' of foods without a knowledge of the historical dynamic of the application of technology and state action to such 'natural' raw materials.

Amount: £51,425
Funder: The Wellcome Trust
Recipient: University of Durham

Density dependent differentiation of mesenchymal cells to endothelial cells 19 Jul 2006

Vascularisation of the Xenopus limb during development and regeneration Regeneration is the ability of a fully developed organism to replace lost tissues, organs and appendages by growth or remodelling of somatic tissue. The most remarkable examples of regeneration in vertebrates occur in amphibians, which are able to regenerate many complex structures. For example these animals are able to regenerate limbs and tails following amputation. Following amputation, epithelial cells begin to migrate as a sheet to cover the exposed mesenchymal tissues; this sheet is known as the wound epidermis. After wound closure the tissue undergoes extensive histolysis and cellular dedifferentiation, whereby the cells lose their differentiated characteristics and become undifferentiated proliferating blastemal cells. The cells contribute to the formation of the blastema; a self-organising cellular mass that forms at the distal end of the amputated stump. The fact that the blastema is comprised of this mass of undifferentiated, proliferating, mesodermal cells likens it to a benign tumour which raises the question as to whether the blastema, like a tumour, requires a vasculature for initiation and continuation of outgrowth. There have been few studies on vasculature formation during regeneration. Early studies in the regenerating limb utilising Prussian blue and Indian ink, led to the conclusion that capillary sprouting begins during wound healing and dedifferentiation stages from vessels in the stump, especially those of the dermis, but that the new capillaries avoid the growing blastema during the early stages of regeneration and only begin to invade the blastema proximally with the onset of histogenesis. Later studies have documented the stages of vessel morphogenesis in regenerating fins, using TG (fli1:EGFP)y1 transgenic zebrafish, as well as the use of a small molecule inhibitor of the VEGF receptor to exert precise control over blood vessel regeneration. This project hopes to elucidate the molecular and cellular mechanisms behind neovascularisation in the developing and regenerating Xenopus limb.

Amount: £133,624
Funder: The Wellcome Trust
Recipient: University of Manchester

The mechanisms of Stim1 translocation in the activation of calcium entry. 19 Jul 2006

A change in intracellular free Ca2+ concentration is an important signalling mechanism that regulates diverse cellular processes. One mechanism for increased Ca2+ entry into cells occurs in response to the emptying of ER Ca2+ stores and involves the ER Ca2+ sensing protein STIM1 and its translocation to the plasma membrane. The first objective is to examine if STIM1 translocation can be observed in HeLa cells in response to store depletion and ATP depletion and to determine whether it inserts into the plasma membrane. The second objective is to investigate the mechanism through which STIM1 moves to and inserts into the plasma membrane. The third objective is to identify novel STIM1-interacting partners that may be involved in translocation or regulation of STIM1. The fourth objective is to examine the dynamic interaction between STIM1 and Orai1.

Amount: £132,687
Funder: The Wellcome Trust
Recipient: University of Liverpool

The investigation of nucleosome dynamics using site directed spin labelling and electron paramagnetic resonance. 19 Jul 2006

WT Studentship for Mr Andrew J Bowman: 4-year PhD studentship in Molecular and Cellular Biology When nuclesomes were first discovered, it was thought they were static bodies, rigid complexes whose function was to package the genome into cellular dimensions. Contrary to this, within the last 15 years or so, nucleosomes have been shown to be highly dynamic entities. Widom and colleagues have shown that DNA wrapped around the histone octamer undergoes spontaneous, transient unwrapping, allowing access to DNA binding proteins. Studies carried out by the Prunell and Victor labs have indicated structural changes in the histone core, particularly in the (H3-H4)2-tetramer. In agreement with this, studies carried out by Cleveland and colleagues on the H3 variant CENP-A showed that certain regions of the tetramer have greater dynamicity. During my rotation project I employed the technique of Site-Directed Spin Labelling (SDSL) and Electron Paramagnetic Resonance (EPR) to further investigate the structural dynamicity of the (H3-H4)2-tetramer. The tetramer is a likely nucleosome folding intermediate, first associating with DNA to form a tetrasome, followed by the binding of H2A-H2B to form the nucleosome proper. However, there is no structural information on the tetramer or tetrasome as a free entity. Another region of the nucleosome which is lacking structural information, though of great biological importance, are the histone tails. It is the general consensus that histone tails are devoid of secondary structure, protruding from the nucleosome into solution as a random coil. In the crystal structures of nucleosomes all but one of the histone tails do not reside in defined positions, the exception making inter-nucleosomal contracts, and thus are not resolved.

Amount: £133,027
Funder: The Wellcome Trust
Recipient: University of Dundee

Do O-GlcNAcases from pathogenic bacteria target specific host cell phosphorylation sites? 19 Jul 2006

WT Studentship for Ms Marianne Schimpl: 4-year PhD studentship in Molecular and Cellular Biology The modification of intracellular and nuclear proteins with O-GIcNAc was first discovered in 1983, and has since been demonstrated to occur on proteins involved in all aspects of cellular metabolism, such as transcription and translation, energy metabolism, cytoskeletal regulation and stress response. In its nature a dynamic modification, the half-life of the O-GIcNAc is shorter than that of the modified protein, in fact it cycles, on a time-scale and in a manner similar to protein phosphorylation. Not surprisingly therefore, O-GIcNAcylation has been implicated in normal cell cycle progression, and just like O-phosphorylation, O-GIcNAcylation occurs on sereine or threonine residues of target proteins. Competitive occupancy of the same site (the so-called 'yin-yang relationship') has been reported, as well as adjacent sites influencing each other, or a combination of both. This discovery adds a degree of additional control onto the binary on/off model assumed for phosphorylation; suggesting that the biological effects cannot be attributed to a single modification. This project is aimed at studying the hypothesis that bacterial enzymes capable of hydrolyzing the O-glycosidic linkage could interfere with specific host cell signal transduction pathways in order to attenuate the host immune response, similar to what has been shown for the Yersinia YopJ acetyle transferase and YopH tyrosine phosphatise.

Amount: £133,027
Funder: The Wellcome Trust
Recipient: University of Dundee

Structural studies of the Sulphonylurea receptor subunit of the ATP-sensitive potassium channel by electron crystallography and molecular modelling. 12 Jun 2006

Structural studies of the Sulphonylurea receptor subunit of the ATP-sensitive potassium channel by electron crystallography and molecular modelling To understand the relationship between KATP channel structure and function, for example how mutations cause neonatal diabetes and where nucleotides and drugs bind, we need structural information of the individual subunit proteins and the way these subunits interact within the KATP channel complex. This project aims to provide that information in two ways: by molecular modelling and simulation of the SUR1 subunits and their interaction with Kir6.2, and by determining the structure of SUR1 in two-dimensional crystals by electron crystallography. Determining structures of large eukaryotic membrane proteins to even near-atomic resolution is notoriously difficult. However, our current studies indicate that the electron crystallography approach is feasible and should result in a SUR1 structure at sub-10Å or better resolution within three years. Consequently, this proposal is structured into three parts which can be addressed independently but have obvious beneficial synergies. We expect that the proposed combination of different threads such as (i) cryo-electron microscopy, (ii) models based on existing ABC transporter structures, using established and novel modelling techniques, and (iii) a structural reinterpretation of existing functional data will lead to a better understanding of SUR1 and KATP channel structure over the course of this PhD project. Part 1: Two-dimensional crystallisation of purified SUR1 and SUR2 protein and method development in the image processing of micrographs of two-dimensional crystals. Part 2: Homology modelling and molecular dynamics simulations of SUR and the KATP channel. Part 3: Developing systematic methods for the interpretation of medium resolution structural data of membrane proteins.

Amount: £138,215
Funder: The Wellcome Trust
Recipient: University of Oxford

Insights into the molecular mechanisms and dynamics of translocation through SecYEG: an approach using ensemble and single molecule techniques. 22 May 2006

1.    Insights into the molecular mechanisms and dynamics of translocation through SecYEG: an approach using ensemble and single molecule techniques Signal sequence-bearing secretory pre-proteins, and integral membrane proteins are translocated either through the inner membrane in bacteria or the endoplasmic reticulum in eukaryotic cells. The main secretory pathway in Escherichia coli involves the SecYEG translocon, which consists of three integral inner membrane proteins: SecY, which forms the protein channel, SecE that forms a clamp around the complex and SecG. A plethora of studies demonstrated that SecYEG undergoes large and complex sequential intramolecular conformational changes upon binding of partner proteins (e.g. SecA or ribosome) and translocation of secretory proteins. However, the nature of the open and closed states, the oligomeric organisation, the regulation of channel gating and the dynamic behaviour of the reaction remain poorly understood. The emergence of fluorescence techniques at the single molecule level has already improved our understanding of such dynamic processes. In-house developments in single molecule fluorescence spectroscopy instrumentation, combined with the expertise of the Radford group in protein folding and the Baldwin group in membrane proteins, place us in a strong position to unravel the SecYEG dynamics and conformational changes involved in protein translocation through this protein pore. The aims of the project are to: (a) Design structure-based FRET labelled mutants of SecYEG, focusing on key domains of the translocon (e.g. "plug domain", "hinge region", dimerisation interface and the two halves of SecYEG, and (b) characterise the structure/function relationship of these labelled SecYEG mutants using ensemble techniques. Measure intra- and intermolecular distances within and between SecYEG and the model substrate proOmpA during translocation using single molecule FRET (smFRET). Determine the extent to which restricting the movement of key domains by "locking" the protein in specific conformations can influence SecYEG function and derive a detailed mechanistic model for protein translocation.

Amount: £130,015
Funder: The Wellcome Trust
Recipient: University of Leeds