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5Th ISMB Retreat, 3-4 July 2013 5th ISMB Retreat 3 – 4 July 2013 Report by Dr. Clare Sansom, Department of Biological Sciences, Birkbeck The Institute of Structural Molecular Biology 2001, Cambridge. He has received numerous (ISMB), set up to foster collaboration honours and awards and is a Fellow of the between researchers in University College Royal Society and a Foreign Member of the London and Birkbeck who work in molecular National Academy of Sciences of the US. and structural biology and allied disciplines, is now ten years old. It has established two Dobson’s research has been particularly series of biannual research meetings focused on the mechanisms through which designed to grow these collaborations, proteins fold, or on some occasions misfold. inspire research excellence and encourage This area of science has become increasingly new ideas. The ISMB symposia, held in even important because of its link with human years, feature lectures by world-class disorders and strategies through which they researchers in its constituent disciplines, and can be combatted. Dobson’s recent work is the residential retreats, held in odd years, summed up in the title of his talk: ‘New are dominated by talks by postgraduate Approaches to Understanding and Preventing students and young postdoctoral researchers Neurodegenerative Diseases’. He began with from its core departments. The retreat held a discussion of this group of diseases, on July 3 and 4 2013 was therefore the fifth explaining how the prevalence of in the series. It was also the third to be held neurodegenerative disorders, and in the quiet surroundings of Robinson College Alzheimer’s disease in particular, is in Cambridge. About 120 delegates, almost increasing dramatically as the population all of whom are affiliated to Birkbeck or ages and how, unless there is a dramatic UCL, took part in a fascinating programme of improvement in the therapies available, the science that included three keynote lectures yearly cost of caring for people with this by brilliant senior researchers and ten short condition will challenge the health care talks by students and postdoctoral systems of the much of the world. For researchers. A poster session and an activity example, the estimated costs of Alzheimer’s intriguingly titled “Professional Speed diseases in the USA will rise from $172 billion Dating”, which was designed to expose the in 2010 to over a trillion dollars by mid- younger delegates to a wide variety of century. careers in science, completed the scientific programme. Alzheimer’s disease is a classic example of a “protein misfolding” or “amyloid” disorder. The retreat was opened by Gabriel Most but not all proteins need to fold into a Waksman, head of both the Department of unique and often highly intricate structure in Biological Sciences at Birkbeck and UCL’s order to perform their functions, and this is Research Department of Structural and a fascinating and complex process, Molecular Biology and founder director of the particularly in the crowded environment of a ISMB. He welcomed delegates to Cambridge living cell. Dobson drew attention in this and to Robinson College and introduced the context to the work of John Christodoulou at first keynote speaker, Professor Chris UCL who has made remarkable progress in Dobson of the Department of Chemistry at defining in molecular detail the process the University of Cambridge and Master of through which a nascent protein chain folds St. John’s College there. Dobson’s research as it leaves the ribosome. He also discussed career has included periods at three of the the various ways in which proteins that mis- world’s leading research universities: first fold can cause disease. Alzheimer’s disease Harvard as a young Principal Investigator in is only one of over 50 different diseases in the late 1970s, then Oxford and finally, since which the protein involved folds into an 5th ISMB R etreat – 3-4 July 2013 1 aberrant structure known as an “amyloid may, or may not, share their chemistry or fibril”, and can become deposited in specific their catalytic residues, and that this precise cells or tissues. Unlike correctly folded relationship can relate to the evolutionary proteins, the amyloid “fold” is not encoded origin of the proteins. She is intending to in the amino acid sequence. Many proteins, apply the technique to proteins from the and even polymers of single amino acids, can large, diverse bacterial populations that are under some circumstances form amyloid found in environments such as the human structures with very similar underlying gut. characteristics. Mun Peak (Peg) Nyon from the Department A key detailed molecular model for a “cross- of Biological Sciences at Birkbeck gave the beta” amyloid structure, stabilised by main next talk. She returned to the theme of chain – main chain hydrogen bonding, was Dobson’s keynote lecture, protein misfolding determined in conjunction with Birkbeck’s diseases, in describing her work on the Helen Saibil using cryo-electron microscopy molecular mechanisms of alpha-1 antitrypsin more than a decade ago, and this deficiency. In this disease, mutations in the collaboration has recently led to the first protein alpha-1 antitrypsin cause the protein complete, atomic resolution structure of an to mis-fold and accumulate in the amyloid fibril. Dobson believes that almost endoplasmic reticulum within cells. She any protein may mis-fold into this structure, described the technique she used to study although some will do so much more readily these deposits as a “bottom-up method”, than others. Understanding the detailed starting with an analysis of the proteome of mechanism of this process provides key the endoplasmic reticulum from healthy and insights into the molecular origins of this diseased cells with and without doxycycline class of diseases: Dobson and his colleagues (which is known to induce alpha-1 antitrypsin in Cambridge and elsewhere are now expression). Over a thousand proteins were developing strategies for the design of small identified in one or more samples and 448 molecules and other therapeutics that can were found to be common between them all; interfere with the process of amyloid the ER fraction from diseased tissue treated formation and that may therefore halt the with doxycycline contained the highest progression of Alzheimer’s and many other concentration of alpha-1 antitrypsin. She is devastating diseases. now examining the quantitative changes in protein expression between the different This lecture was followed by the first three conditions with the aim of identifying novel of the short talks by student and response mechanisms in alpha-1 antitrypsin postdoctoral members of the ISMB. Natalie deficiency and other diseases involving the Dawson , a PhD student in Christine Orengo’s endoplasmic reticulum. bioinformatics group in the Research Department of Structural and Molecular Biology at UCL had the challenging task of Paul Moody , a Wellcome Trust funded PhD following immediately after Dobson. She student in the Department of Chemistry at described her work on the automatic UCL gave the next talk. He described the use annotation of protein sequences by function. of green fluorescent protein (GFP) as a Although it is becoming easier to annotate model protein for the development of protein sequences structurally as the techniques to functionalise small, tractable proportion of known folds grows, functional protein scaffolds as biotherapeutics. Many annotation of novel sequences is more proteins have been designed as therapeutic challenging. The Orengo group has agents, but the largest class of these – developed a tool for dividing proteins into antibodies – are large enough molecules to classes based on their predicted functions, be difficult to express and study. Protein and has classified the proteins in each of therapeutics are ideally homogeneous and CATH’s structure-based super-families into can benefit from being modified chemically. these so-called ‘FunFams’. Dawson described Moody and his colleagues are developing a classifying enzymes of known structure using technique for the chemical modification of this method, showing that the functional proteins that involve the incorporation of sub-families in a given enzyme super-family both dehydroalanine and sulphonium into the 5th ISMB Retreat – 3-4 July 2013 2 protein chain in the place of cysteines. They Sazanov described the overall L-shaped have proved the principle of these structure of the complex, with a techniques by incorporating functional hydrophobic, membrane-spanning base and a groups into GFP, and are hoping to adapt hydrophilic arm located in the cytoplasm them so that it is possible to incorporate that binds a string of nine iron-sulphur more useful molecules, including drugs. clusters. The base includes three similar antiporter-like subunits, each of which The afternoon’s scientific presentations contains 14 conserved transmembrane ended with the second keynote lecture, by helices, and each of which can translocate a Leonid Sazanov from the MRC Mitochondrial single proton across the membrane. Biology Unit in Cambridge. Sazanov, However, the proton channel in each of originally from Belarus, had reached his these subunits is seen to be “broken” into present position via Minsk and Moscow, and two half-channels that are separated in then Birmingham University and Imperial space. College in the UK. His talk described some elegant structural biology carried out by his The structure of one further transmembrane group in elucidating the structure of the subunit, known as Nqo8/ND1, has proved to largest of the protein complexes that carry be the last remaining key of the puzzle to out the crucial metabolic task of respiration. understand the mechanism of action of the whole complex. This, which is the most Respiratory complex I is a huge – in conserved of all the hydrophobic subunits in molecular terms – “molecular machine” that the complex, has a fold that is similar to half is embedded in the membranes of both an antiporter protein. Further membrane- mitochondria and bacterial cells.
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