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ISMB News


This page contains recent ISMB News items. Previous ISMB news items are available in the archive.

Latest ISMB Newsletter

The latest ISMB newsletter (Summer 2014) can be read here.

 

Amandine Maréchal awarded MRC Career Development Award

November 2014

Dr Amandine Maréchal (Prof Peter Rich's group) has been awarded a prestigious MRC Career Development Award with a project entitled 'cytochrome c oxidase's structure, function and malfunction'. This fellowship will provide her and her lab with £1,3m over 5 years to address key questions relating to the molecular mechanism of this central respiratory enzyme and its implication in mitochondrial diseases. It is centred on the use of a yeast system that allows, for the first time, production and large scale purification of mitochondrial mutant forms of the enzyme. Prof Shamima Rahman (UCL ICH), Dr Brigitte Meunier (CNRS, France) and Dr Leonid Sazanov (MRC MBU, Cambridge) are partners of her project.

 

ISMB student wins poster prize at UCL Division of Biosciences PhD Symposium

November 2014

Congratulations to Pavi Rallapalli, from Prof Steve Perkins' group in the Research Department of Structural and Molecular Biology, who won the poster prize at the Biosciences PhD Symposium that took place on 5 November.

 

Elizabeth Rodriguez and Ruodan Nan receive prizes at XXV International Complement Workshop in Rio
October 2014

Congratulations to Elizabeth Rodriguez and Dr Ruodan Nan, PhD student and Post-Doc respectively from Prof Steve Perkins' group, who won prizes at the 25th International Complement workshop in Rio De Janeiro in September. Among 59 oral presentations and 216 posters, the prizes received were among only 7 awarded.

Elizabeth Rodriguez received the prize for best oral presentation for her talk, 'A revised mechanism for the activation of complement C3 to C3b and a molecular explanation of the difference between their C3S and C3F polymorphic forms'.

The talk explained how the structural effect of the R102G polymorphism in C3b causes AMD and aHUS. It had been presented previously at an ISMB Friday Wrap on 30 May 2014. The paper on the work has recently been accepted for publication in the Journal of Biological Chemistry.

Dr Ruodan Nan won the prize for best abstract for her submission entitled, 'An extended 1:1 complex between complement C3b and factor H on biosensor surfaces clarifies the regulatory mechanism of the complement alternative pathway at cell surfaces'.

[Posted: October 2014]

 

Featured Publication

October 2014

Allosteric signalling in the outer membrane translocation domain of PapC usher

PapC ushers are outer-membrane proteins enabling assembly and secretion of P pili proteins in uropathogenic E. coli, allowing them to infect the human urinary tract and cause disease. To pass through the outer membrane of the E. coli cell, a P pili protein must travel through the translocation domain of PapC. The translocation domain is a large β-barrel occluded by a middle domain (plug domain), which is only marginally stable, to allow the opening of the barrel. Previous studies suggested that this gating mechanism is controlled by two elements of the translocation domain – a β-hairpin and an α-helix, but it is not clear how.

To investigate the role of these elements in allosteric signal communication, we developed a hybrid computational method combining evolutionary and molecular dynamics studies. Our starting point was molecular dynamics simulations on 4 different models: the native protein structure, two mutants in which the helix or β-hairpin is deleted, and a mutant in which both are deleted. Polar interactions observed during the simulations were compared in all systems in order to detect interactions that change upon mutation. Additionally, we used evolutionary analysis, relying on both amino acid conservation and coupling (co-evolution) to highlight particularly important interactions. The data were combined in a large hybrid residue interaction network. Using graph theory approaches, we showed that certain regions of the β-barrel, located mostly on one side of the barrel, are likely involved in moving the plug domain. This unique computational approach allowed us to detect key amino acids in these distinct regions (residue ‘communities’) that likely control the position of the plug in the pore, thereby regulating PapC gating and usher’s activation.

The predictions were tested by experiments, in collaboration with the Waksman group and two groups in the US – Delcour group at the University of Houston and Thanassi Group at Stony Brook University. Antibiotic sensitivity and electrophysiology experiments on a set of alanine-substitution mutants confirmed functional roles for four communities. Our results suggest that residues around β12–β14 that are beneath the α-helix act as a regulator of β 12- β 13 loop (the ‘latch’) that controls the opening and closing of the β-barrel. Taken together, the study illuminates the gating mechanism of PapC ushers and its importance in maintaining outer-membrane permeability.

Farabella I, Pham T, Henderson NS, Geibel S, Phan G, Thanassi DG, Delcour AH, Waksman G, Topf M. Allosteric signalling in the outer membrane translocation domain of PapC usher. eLife. 2014 Oct 28; e03532; DOI: http://dx.doi.org/10.7554/eLife.03532.

Test1c

[Posted: October 2014]

 

Featured Publication

October 2014

Taking Steps Towards Elucidation of Kinesin Motor Mechanochemistry

In the crowded environment of a eukaryotic cell, long-distance active transport by molecular motors is essential. Cellular dysfunction and disease - including paralysis and neuropathy - ensues when these transport processes break down.

Kinesins are a superfamily of motors that move along microtubule tracks within the cytoplasm, powered by energy from ATP binding and hydrolysis. Kinesins are defined by their conserved motor domains, which contain both ATP- and microtubule-binding sites. The rest of the kinesin molecule extends away from the microtubule. Dimerization is mediated by coiled-coil formation between two protomers. At the distal end of the dimeric molecule, cargo – such as vesicles and mitochondria - are attached to allow transport to their appropriate cellular destination. The two kinesin chains within the dimer work together to take directional steps along the microtubule, powered by ATP.

To take these steps, each kinesin motor domain in the pair must undergo alternating cycles of tight association and release from their tracks. This cycle is coordinated by binding and breakdown of ATP, which also provides the energy needed to take the next step. How the cycle of loose and tight microtubule attachment is coordinated with release of the breakdown products of ATP, and how the energy from the ATP molecule is converted into the force that moves the motor along the microtubule, has been unclear.

Answering structural questions about motor mechanism is challenging because high spatial resolution is needed to study conformations that usually only last fractions of a second. In addition, the complexes formed by kinesins and their microtubule tracks are large and dynamic. We solved these challenges by determining a sequence of structures using cryo-electron microscopy and image reconstruction. We thereby obtained multiple snapshots– in more detail than previously seen (at ~7Å resolution) – of the motor domains of two types of kinesin, called kinesin-1 and kinesin-3. In collaboration with Maya Topf’s group, we also calculated pseudo-atomic models of these motors.

Our structures show the way in which interaction with the microtubule causes shape changes in the motor domains to stimulate release of the breakdown products of ATP from the previous cycle. This release makes room for binding by a new ATP molecule. When ATP binds, it in turn causes structural changes that allow the next step to be taken. This mechanism involves tight coupling between track binding and fuel usage and makes kinesins highly efficient motors. Previously, kinesin-1 and kinesin-3 were thought to move along the microtubule tracks in different ways; however, our structures show that the core mechanism used by their motor domains is, in fact, the same. Our new structures also provide unprecedented insight into how the stepping mechanism can be disrupted by disease-causing mutations in the kinesins. Future work will clarify whether the key features observed in the motor domains of kinesin-1 and kinesin-3 are also found in other types of kinesin motors. This work was funded by the MRC. Joe Atherton will present this work at a Friday Wrap (24/10/14).

Atherton J, Farabella I, Yu IM, Rosenfeld SS, Houdusse A, Topf M, Moores CA. Conserved mechanisms of microtubule-stimulated ADP release, ATP binding and force generation in transport kinesins. eLife. 2014 Sep 10:e03680. doi: 10.7554/eLife.03680. [Epub ahead of print]

striking

[Posted: October 2014]

 

Dr Matthew Gold receives Sir Henry Dale Fellowship
October 2014

Congratulations to Dr Matthew Gold on being awarded a Sir Henry Dale Fellowship from the Wellcome Trust/ Royal Society.

[Posted: October 2014]

 

Professor Helen Saibil receives honorary fellowships
October 2014

Congratulations to Prof Helen Saibil, who has received honorary fellowships for both the British Biophysical Society and the Royal Microscopial Society in their 2014 honours lists.

[Posted: October 2014]

 

New Fellows in the Department of Biological Sciences, Birkbeck
October 2014

Welcome to Drs Giulia Zanetti and Anthony Roberts, beginning as Fellows in the Department of Biological Sciences, Birkbeck in October and November 2014 respectively.

Giulia Zanetti has been a post-doc in the department since Summer 2013 and recently received a Royal Society Dorothy Hodgkin Fellowship to run for 5 years from 1 October 2014.

Anthony Roberts joins the Department on 1 November from Harvard Medical School, on a 5 year Wellcome trust/Royal Society Sir Henry Dale Fellowship.

[Posted: October 2014]

 

ISMB Core Member Promotions
October 2014

Congratulations to the following on their promotions within the Department of Biological Sciences, Birkbeck:

[Posted: October 2014]

 

Wellcome Trust Multi User Equipment Award for 'Using Structural Mass Spectrometry for the Study of Large Macromolecular Machines'
August 2014

Congratulations to Prof Gabriel Waksman and co-applicants Prof Jürg Bähler, Helen Saibil, Trevor Smart, Finn Werner, John Christodoulou and David Lomas and Dr Konstantinos Thalassinos, who have received a Wellcome Trust Multi-User Equipment Award of up to £205,468 for the project, 'Using Structural Mass Spectrometry for the Study of Large Macromolecular Machines'.

[Posted: September 2014]

 

Dr Alan Lowe receives funding for Holographic Super-Resolution Microscope from LMCB, UCL
August 2014

Congratulations to Dr Alan Lowe, who has been awarded UCL New Microscopy Developments Funding of £95,000 for purchase of a Holographic Super-Resolution Microscope, by the Laboratory for Molecular Cell Biology (LMCB), UCL.

[Posted: September 2014]

 

Professor Chris Kay awarded Fellowship by Japan Society for the Promotion of Science
August 2014

Congratulations to Professor Chris Kay, who has been awarded a Short-Term Invitation Fellowship by the Japan Society for the Promotion of Science (JSPS). The JSPS Invitation Fellowship Program is a competitive scheme whereby overseas researchers with excellent records of research achievements can visit Japan for the purpose of contributing to the advancement of research though discussions, opinion exchanges, lectures and other means. Professor Kay commented: I am delighted to have been selected for this prestigious programme. The Fellowship will enable me to make an extended visit to work with my colleagues in Japan and deepen our existing collaborations in quantum biology. My host, Professor Mino Hiroyuki, at the University of Nagoya, and I are working together on the spin physics of photosynthesis, so the project brings together my interests in organic spintronics and structural biology.

[Posted: September 2014]

 

Cipla Distinguished Fellowship for Dr Sanjib Bhakta
August 2014

Dr Sanjib Bhakta, Reader in Molecular Microbiology and Director of Mycobacteria Research Laboratory (MRL) in the Department of Biological Sciences and the Institute of Structural and Molecular Biology, has been awarded a prestigious Cipla Distinguished Fellowship in Pharmaceutical Sciences for his outstanding research on tackling antibiotic resistance in tuberculosis.

On his trip to India in July, Dr Bhakta gave the Cipla endowment lecture entitled Tackling antibiotic resistance in TB at the University Institute of Chemical Technology (ICT), Mumbai (India). In his lecture, Dr Bhakta spoke about inter-disciplinary approaches in novel therapeutic intervention to tackle drug resistance in M. tuberculosis and discussed techniques developed exclusively in his laboratory to evaluate potential anti-infective molecules. Highlighting some of the current work being carried out in his laboratory Dr Bhakta spoke about understanding ligand-protein interaction to unveil the mechanisms of action of anti-mycobacterial compounds. Dr Bhakta’s lecture will be published in the annual journal of ICT, the Bombay Technologist.

During his visit to ICT, Mumbai, Dr Bhakta also met the departmental heads, academic course coordinators and deans and offered a career acceleration mentoring session for graduate researchers and post-doctoral students. Collaboration between ICT and Birkbeck's Mycobacteria Research Laboratory is not new and existing relations will be consolidated and developed in the future, once a draft material transfer agreement and memorandum of understanding is implemented. In addition, a group of distinguished professors from ICT will visit Birkbeck later this year. Collective work between these two universities will benefit from the availability of potential anti-tubercular agents of natural, semi-synthetic and/or synthetic origin and the technical expertise of Dr Bhakta in evaluating the effectiveness of these novel agents towards new anti-infective drug development.

While in India, Dr Bhakta also visited a number of other universities, colleges, research institutes and non-governmental organizations to shed light on the world-class research being carried out by MRL researchers in the field of tuberculosis drug design and to discuss new health and diseases research and educational initiatives between UK and India. Dr Bhakta has been working with the Indian Development Foundation (IDF) since 2009 and this year he was elected as IDF’s honorary international consultant for TB research. Established in 2005, the IDF is a non-government organisation with goals to improve education, development and health in rural parts of India. Its activities have been key in the elimination of leprosy in India, and it is now focused on combatting tuberculosis and other diseases.

You can read more about Dr Bhakta’s recent seminars at educational institutions across India, describing his team's groundbreaking research on antibiotic resistance in TB.

[Posted: September 2014]

 

ISMB Core Member Promotions
July 2014

Congratulations to the following on their promotions within the Research Department of Structural and Molecular Biology, UCL:

[Posted: July 2014]

 

2014 Lister Institute Research Prize awarded to Dr Emmanuel Boucrot
June 2014

Dr Emmanuel Boucrot, BBSRC David Phillips Fellow, has been awarded a prestigious Lister Institute Research Prize. These annual awards are made by The Lister Institute to support young scientists undertaking high quality research in biomedical science or related scientific areas in the UK. Prize holders also become members of the Lister Community of Fellows.

The Prize award, which includes £200,000 over five years, will enable Emmanuel to study a new pathway of endocytosis he and his co-workers recently discovered. The main focus of the investigations will be to identify receptors that use this pathway to enter into cells and to reveal the components that generate the endocytic carriers. This will allow his laboratory to dissect how cells modulate the levels of medically important receptors at their surface.

[Posted: July 2014]

 

ISMB Symposium 2014
June 2014

The sixth biennial ISMB research symposium was held in mid-June 2014 in Birkbeck’s Clore Management Centre. Its packed two-day scientific programme followed the pattern of previous symposia, featuring fifteen excellent lectures from both distinguished researchers and rising newcomers.

The programme was divided into sections covering all the Institute’s research areas, with a sixth discipline, proteomics and mass spectrometry, added to those covered in 2012: structural biology, computational biology, biophysics, chemical biology and biochemistry with cell biology. One speaker in each section was a core member of the ISMB. The symposium was supported by both Birkbeck and UCL at the highest level; it was opened by Geraint Rees who is shortly to take on the role of Dean of the Faculty of Life Sciences at UCL, and closed by Nicholas Keep, who holds an equivalent position at Birkbeck. Both deans paid tribute in their remarks to the vision, energy and leadership of the Institute’s director, Gabriel Waksman.

For the first time in its 12-year history, the ISMB had the honour of welcoming a Nobel laureate as a symposium speaker. This was Venki Ramakrishnan, whose share of the 2009 Nobel Prize for Chemistry was awarded for structural studies of the ribosome. He described his most recent structure, the first high-resolution structure of the large subunit of a mitochondrial ribosome. The tunnel through which a growing protein chain emerges from this ribosome takes a different path, possibly to position the protein close to the mitochondrial membrane.

The other external speaker on structural biology, Werner Kühlbrandt from Frankfurt, Germany, described the structure of a human ion transport protein and showed how the organisation of the mitochondrial membrane is disrupted during ageing. In an inspiring talk, Shankar Balasubramanian from the University of Cambridge described how his research into DNA synthesis led to the development of a solid-state technique for DNA sequencing that is many orders of magnitude faster than those used in the 15-year long Human Genome Project. Thanks in part to this technology it is now possible to sequence a dozen or so human genomes in a few days. Despite this success, Balasubramanian still works in basic research, using DNA sequencing with simple chemistry to distinguish between different modifications of the base cytosine.

A number of other speakers also described research into nucleic acids and their interactions with proteins. Achilles Kapanidis from the University of Oxford described using a fluorescence-based technique, single-molecule Főrster resonance energy transfer (FRET) as a “molecular ruler” to investigate structures formed during the process of DNA transcription that are too transient to be observed using more traditional methods. Albert Heck from Utrecht University in the Netherlands described a protein-RNA complex termed Cascade, which helps to defend bacteria against attack by viruses. His group used mass spectrometry to determine this unusual, spiral structure. And, speaking in the chemical biology section, Christopher Hunter from the University of Sheffield explained how his group used computational techniques to predict the way that DNA winds round proteins to pack into the cell nucleus.

In the cell biology programme, Marino Zerial from Dresden, Germany, presented a new model for liver tissue structure with an ordered network of capillaries and bile channels, and UCL’s Alison Lloyd explained the mechanism through which nerve cells regenerate following injury. Soren Brunak from the Technical University of Denmark presented an unexpected aspect of computational biology in discussing his automatic analysis of medical records. This has uncovered some unexpected genetic linkages, for example, finding one gene – THRA - that links male pattern baldness with migraine.

The next ISMB symposium will take place in June 2016.
A full report of the 2014 symposium is available at http://www.ismb.lon.ac.uk/symposium.html.

[Posted: July 2014]

 

Research by Dr Kate Bowers into Developing Novel, In Vivo Assays for Eukaryotic Membrane Fusion
May 2014

Dr Kate Bowers of the ISMB is among a group of scientists who have developed novel assays for eukaryotic membrane fusion in vivo. Membrane fusion in eukaryotic cells is an essential cellular process involved in (for example) organelle biogenesis, protein trafficking, fertilization, muscle biogenesis and pathogen invasion. In vitro studies in yeast, using purified vacuoles, have been instrumental in determining the cellular machinery required for membrane fusion. These studies have implicated the vacuolar H+-ATPase (V-ATPase) as part of the fusion machinery. The V-ATPase is a multisubunit, rotary proton pump, and models formulated from in vitro yeast studies suggest that it is the proteolipid proton-translocating pore of the V-ATPase that functions in fusion, with further studies in worms, flies, zebrafish, and mice supporting this model.

Some years ago, Kate Bowers and Nia Bryant (University of Glasgow*) set up a new assay to measure membrane fusion in vivo. Using this assay, they were able to show that the proteolipid proton-translocating pore of the V-ATPase is not part of the fusion machinery. Complementary experiments, using another in vivo assay developed by Tom Stevens and his group (University of Oregon) supported this conclusion. The team from UCL, Glasgow and Oregon were then able to show conclusively that while acidification is required for the fusion of yeast vacuoles, the physical presence of the V-ATPase is not. This work is important as it will lead to a re-evaulation of models of membrane fusion in yeast and higher organisms, and ultimately to the greater understanding of this essential cellular process.

* now Chair of Cell Biology at the University of York.

[Posted: May 2014]

 

Biosciences staff win UCL Provost's Teaching Award 2014
May 2014

A warm congratulations to some of our Biosciences staff for winning one of the elite UCL Provost’s Teaching Awards for 2014.

Dr Andrea Townsend Nicholson, Dr Amanda Cain, Charmian Dawson, Dr Chris Taylorson, Dr Suzanne Ruddy and Professor Elizabeth Shephard were winners of an award for Team Collaboration and Achievement in Teaching.

The team will be presented with its award at a ceremony taking place on Monday 9 June at the Institute of Child Health, Guildford Street.

[Posted: May 2014]

 

Professor Christine Orengo elected member of EMBO
May 2014

Congratulations to Professor Christine Orengo who has been elected as a new member of EMBO in recognition of outstanding research in the life sciences. Professor Orengo (UCL Division of Biosciences) was one of 106 “outstanding researchers in the life sciences” that were elected to be European Molecular Biology Organisation (EMBO) members in 2014.

Christine Orengo’s research has focused on how proteins evolve – how do relatives in a family diverge in structure and function and how do they evolve to operate in different biological contexts. Nearly 20 years ago she established the CATH classification of protein domains, together with Janet Thornton, which is widely accessed (nearly 2 million webpage accesses and 10,000 unique visitors per month) and a partner resource in InterPro.

CATH was enabled by the development of robust protein structure comparison algorithms, (SSAP - JMB 1989, CATHEDRAL – PloS Comp Biol 2007) still used by the structural biology and structural genomics communities. Her group participate in two large structural genomics initiatives which exploit CATH for targeting pathogenic proteins (JMB 2005, Structure 2009). Analysis of CATH led to important insights into the population of structural families and folds (Nature 1994) and revealed the bias in protein domain families whereby less than 5% account for two thirds of all known domains (Annual Reviews Biochem. 2005, NAR 2006).

CATH analyses also revealed expansions of functional repertoires in bacteria (TIG 2005), novel structural motifs (Structure 1993) and structural mechanisms mediating changes in protein functions (JMB 2006, TIBS 2009, Structure 2010). More recently, with the assignment of 20 million domains to CATH, sequence analysis has enabled the recognition of functional subfamilies possessing distinct sequence patterns that can aid function prediction (NAR 2010, Nature Methods 2012). The group also study evolution of functions in CATH superfamilies (TIBS 2002, PNAS 2013). CATH domain families have also been exploited in the prediction and analysis of protein networks (PLoS Comp Biol 2009, Pain 2013) and the group collaborate with several experimental groups characterising signalling networks implicated in development, neuropathic pain and cancer.

[Posted: May 2014]

 

Prof Steve Perkins Receives Alexion Educational Grant
April 2014

Congratulations to Professor Steve Perkins, who has been awarded a grant for a 4 year PhD studentship by Alexion Pharmaceuticals and Complement UK.

[Posted: April 2014]

 

Research by the Waksman Lab into Bacterial Secretion Sheds Light on Antibiotic Resistance
March 2014

A team of scientists led by Professor Gabriel Waksman has uncovered the system that allows the sharing of genetic material between bacteria, and therefore the spread of antibiotic resistance. The research, published in Nature and funded by the Wellcome Trust, reveal the mechanism of bacterial type IV secretion, which bacteria use to move substances across their cell wall.

As type IV secretion can distribute genetic material between bacteria, notably antibiotic resistance genes, the mechanism is directly responsible for the spread of antibiotic resistance in hospital settings. It also plays a crucial role in secreting toxins in infections - causing ulcers, whooping cough, or severe forms of pneumonia such as Legionnaires’ disease. Using electron microscopy the team were able to reconstruct the system as observed in the bacteria E. coli. They saw that the mechanism consists of two separate complexes, one in the outer membrane of the cell, and the other in the inner membrane, which are connected by a stalk-like structure that crosses the periplasm – the space between the two membranes. The complexes at both the inner and outer membranes form pores in the membrane, via which substances can be secreted.

Professor Waksman said: ‘This work is a veritable tour de force. The entire complex is absolutely huge and its structure is unprecedented. It is the type of work which is ground-breaking and will provide an entirely new direction to the field. Next, we need to understand how bacteria use this structure to get a movie of how antibiotics resistance genes are moved around.’ ‘Understanding bacteria’s secretion system could help design new compounds able to stop the secretion process, thereby stopping the spread of antibiotics resistance genes. Given that antibiotics resistance has become so widespread and represents a grave threat to human health, the work could have a considerable impact for future research in the field of antimicrobials.’

Asymmetric Composite Structure of the T4SS3–10 Complex

Asymmetric Composite Structure of the T4SS3-10 Complex

a, Front view. The map is a composite generated by merging independently processed core complex and IMC reconstructions. b, Cut-away front view. Electron density is colour-coded, ranging from red to blue, indicating regions of strong to weak density, respectively. The IMC has pseudo-two-fold symmetry around the particle long axis. c, Side view. U-, M- and L-tier substitute for upper, middle and lower tier, respectively.

  • Click here to read the full article, published in Nature (doi:10.1038/nature13081)

[Posted: March 2014]

 

ISMB Commentary
January 2014

Beyond tumour suppression: p53 is a key regulator of vertebrate regeneration

Salamanders are the champions of regeneration. Unlike mammals, these organisms are able to regenerate an impressive repertoire of body structures, including spinal cord, heart, brain and entire limbs. Understanding how salamanders regenerate complex structures is of great biological interest because it can provide insights into fundamental cellular processes as well as eventually teaching us how to stimulate regeneration in humans. Recent research from ISMB researchers Max Yun, Phillip Gates and Jeremy Brockes has uncovered a new molecular mechanism for controlling the process of salamander regeneration, dependent on the tumour suppressor p53.

The authors sought to understand the molecular mechanisms that control regeneration using the salamander limb as their system. Limb regeneration depends on the reprogramming of differentiated cells within the mature tissues. Upon amputation, these cells dedifferentiate and re-enter the cell cycle to proliferate, forming a mound of progenitor cells called a blastema. These cells can then undergo a redifferentiation process that leads to the restoration of the limb. What are the molecular mechanisms underlying the regulation of such critical dedifferentiation-differentiation processes?

Their research, published in the journal PNAS, shows that regulation of p53 is central to the answer. They found that, as regeneration begins, the salamander temporarily downregulates p53 activity enabling the reprogramming of differentiated cells and their re-entry into the cell cycle. Later on, the organism upregulates p53 to trigger redifferentiation as the new limb is formed. The authors were able to show not only that these changes in p53 activity happen but that they are functionally critical for regeneration.

Regen-Limb
 

How is this strict temporal regulation achieved? The authors suggest a key role for a p53 dominant negative isoform, Np73, which they found to exhibit an inverse pattern of expression through salamander regeneration compared to p53. When its expression was artificially prolonged the redifferentiation phase of regeneration was delayed. Based on these findings, the authors propose that in salamanders the absence of tumour suppressors that stabilise p53 allows p53 activity to fluctuate (albeit under strict temporal control) in a manner which would not be possible in other species. The control of this fluctuation by regulators such as Np73 enables salamanders to execute the precise dedifferentiation and redifferentiation of adult tissue required for limb regeneration.

This research uncovers a key molecular mechanism controlling differentiation and its reversal in vertebrates. Additionally, it provides a new perspective on the functions of the key tumour suppressor p53. It reveals how subtle regulation of p53 is critical to a process which must orchestrate dedifferentiation, proliferation and redifferentiation whilst maintaining strict genomic integrity. Hence, the interplay between p53’s functions in tumour suppression, cell plasticity and development don’t have to be trade-offs. Strict p53 temporal regulation, revealed here in one remarkable species, is permissive for regeneration but retains its acute tumour resistance, a well-established characteristic of this process.

Full article: Maximina H Yun, Phillip B Gates & Jeremy P Brockes. “Regulation of p53 is critical for vertebrate limb regeneration”. PNAS (2013) October 22, 110 (43): 17392-7.

Left: Regenerated salamander limb. The red line indicates the regeneration plane. (Image: Maximina Yun, Phillip Gates & Jeremy Brockes)

[Posted: February 2014]

 

Prof Ivan Gout receives BBSRC Responsive Research Grant
December 2013

Congratulations to Prof Ivan Gout, who has received an award of £474, 000 from BBSRC for the project 'Role of DNA Binding in the Regulation and Function of Ribosomal S6 Kinase 2'.
£386k will be used by Prof Ivan Gout and £88k by his co-investigator Prof John Hartley in the Research Department of Oncology, UCL Cancer Institute.

[Posted: January 2014]

 

Professor Helen Saibil is part of academic team behind new biology imaging centre at Diamond
December 2013

Professor Helen Saibil, Bernal Professor of Structural Biology at Birkbeck, is one of the academic leads for a new imaging centre for biology which will be built at the Diamond Light Source in Oxford. The centre will be funded by a £15.6 million grant from the Wellcome Trust, The Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). The new centre will provide scientists with state-of-the-art experimental equipment and expertise. The powerful cryo-electron microscopes will reveal more of cell structure to help further understand molecular make-up and will provide new tools to visualise single bio-molecules. The facility will offer two high end Cryo-Electron microscopes, a sample preparation laboratory with a super-resolution fluorescence microscope, and equipment for vitreous sectioning with an ion-milling beam.

Read the full press release here.

[Posted: December 2013]

 

Dr Vitor Pinheiro receives ERC 4-year grant
November 2013

Congratulations to Dr Vitor Pinheiro, who has been awarded a ERC grant of just under 1.2M euros.
The grant will begin in February 2014 and will fund two post-docs - one in a 4-year post and one 3-year post with a delayed start.

The funded work focuses on pushing synthetic nucleic acids one step closer to the cell. Dr Pinheiro's previous work has seen him develop enzymes that could interconvert XNA and DNA information. This project will go a step further developing XNA->XNA replication and a viable genetic element in XNA.

[Posted: November 2013]

 

Dr Saul Purton receives BBSRC funding for Network in Algal Biotechnology
November 2013

Congratulations to Dr Saul Purton, whose application for funding for a network in Algal Biotechnology has been accepted by the BBSRC to receive a 5 year award of £1.4M.
The network is one of ten nationally to be awarded on the BBSRC's programme of industrial biotechnology and bioenergy funding announced earlier this year.

[Posted: November 2013]

 

ISMB members awarded Wellcome Trust Sir Henry Dale Fellowships
November 2013

Congratulations to Drs Filipe Cabreiro and Alan Cheung, who have each been awarded a prestigious Wellcome Trust Sir Henry Dale Fellowship.

[Posted: November 2013]

 

Dr Saul Purton awarded four BBSRC 4-year PhD Studentships
October 2013

Congratulations to Dr Saul Purton, who has received 4 BBSRC funded studentships for 2014/15 in response to his Strategic Longer and Larger (sLoLa) grant proposal.

[Posted: October 2013]

 

New book on 'Protein-Ligand Interactions' by ISMB Biophysicists
October 2013

Drs Tina Daviter and Mark Williams at the ISMB Biophysics Centre have edited a new book on Protein-Ligand Interactions, published by Springer.
Experts from around the world have written easy-to-follow protocols for the discovery and characterization of protein-ligand binding. With lots of background information, both theoretical and practical, the book is designed to provide a coherent introduction to biophysics; understandable for beginners and enlightening for experts. These protocols will serve as great resources for current and future users of the ISMB's wide range of biophysics instrumentation.

[Posted: October 2013]

 

ISMB Core Member promotions
October 2013

Congratulations to the following ISMB Core Members on their recent promotions:

  • Prof John Christodoulou (Research Department of Structural and Molecular Biology, UCL) promoted to Professor of Biological NMR Spectroscopy
  • Dr Maya Topf (Department of Biological Sciences, Birkbeck), promoted to Reader in Computational Biology

[Posted: October 2013]

 

Dr Carolyn Moores receives BBSRC Research Grant
October 2013

Congratulations to Dr Carolyn Moores, who has received a Biotechnology & Biological Sciences Research Council (BBSRC) grant of £351,254 over 2 years, starting from January 2014.

[Posted: October 2013]

 

Prof Gabriel Waksman elected to German Academy of Sciences
August 2013

Professor Gabriel Waksman, Head of the ISMB, has been elected to the German National Academy of Sciences or Leopoldina. His election is in recognition of his research into the structural and molecular biology of secretion systems in bacteria. These systems determine bacteria survival, adaptation and evolution, making them ideal targets for developing new antibiotics.

Election to the Leopoldina, the oldest continuously existing academy of medicine and the natural sciences in the world, is the highest academic honour awarded by a German institution. Its membership of 1,400 distinguished scholars is drawn from 30 countries and past members have included such eminent scientists as Marie Curie, Charles Darwin, Albert Einstein and Max Planck.

Professor Waksman commented on his election: "I am delighted to have been elected to this prestigious academy. It not only recognises the quality of the work we've done over the years, but also, cements a strong relationship between my laboratory and laboratories in Germany."

Read more about the work of the Waksman Lab.

[Posted: August 2013]

 

Prof Steve Perkins receives Alexion Pharmaceuticals grant
August 2013

Congratulations to Prof Steve Perkins, who has been awarded a grant of $98,733 for 6 months initially, from Alexion Pharmaceuticals, Inc. The grant will fund one Post Doctoral Researcher.

[Posted: August 2013]

 

Dr Matilda Katan (Principal Investigator) and Dr Christine Orengo (Co-Investigator) awarded CRUK Programme Grant
August 2013

Congratulations to Matilda Katan and Christine Orengo, who have been awarded a CRUK Programme grant worth £975,251 running for at least 4 years from October 2013. The grant will include funding for 4 PDRAs.

[Posted: August 2013]

 

Prof Helen Saibil awarded BBSRC Grant
August 2013

Congratulations to Prof Helen Saibil, who has been awarded a BBSRC grant of £387,500, starting in August 2013 to run over 3 years. The grant will part-fund the purchase of an electron detector.

[Posted: August 2013]

 

Dr Christine Orengo awarded BBSRC Bioinformatics and Biological Resources (BBR) Research Grant
July 2013

Congratulations to Dr Christine Orengo, who has been awarded a BBSRC BBR research grant of £612,409 for four years from January 2014. The grant includes funding for 1 PDRA.

[Posted: July 2013]

 

Dr Lisa Cabrita awarded Alpha-1 Foundation Project Grant
July 2013

Congratulations to Dr Lisa Cabrita, a senior post-doc in Dr John Christodoulou's group, who has been awarded an Alpha-1 Foundation project grant worth $195,935. The grant will run for 2 years from January 2014, and includes funding for 1 PDRA.

[Posted: July 2013]

 

Dr Vitor Pinheiro receives BBSRC grant
June 2013

Congratulations to Dr Vitor Pinheiro, who has been awarded a BBSRC grant worth £459,002. The grant will fund 1 PDRA.

[Posted: June 2013]

 

ISMB Graduate Symposium, 11-12 June 2013
June 2013

This annual event is designed to give PhD students at the ISMB the opportunity to present their work and is typically attended by over 100 PhD students and supervisors.

The 2013 ISMB Graduate Symposium will take place on Tuesday 11 and Wednesday 12 June in the JZ Young Lecture Theatre, Anatomy Building, UCL.

Professor Liz Shephard, Research Department of Structural and Molecluar Biology, will be the guest speaker.

Full programme details will be circulated among members of the ISMB soon.

[Posted: May 2013]

 

UCL student wins Eisenthal Prize to work with Professor Steve Perkins
May 2013

Congratulations to Anna Miles, a second year Biochemistry student at UCL, who was this year's winner of the Biochemical Society Eisenthal Prize to carry out a summer studentship project with Prof Steve Perkins at UCL.

[Posted: May 2013]

 

Featured Publication
April 2013

Structural and Energetic Basis of Folded-Protein Transport by the FimD Usher


Geibel S., Procko E., Hultgren S.J., Baker D., Waksman G. Nature 496, 243–246, doi:10.1038/nature12007

Published this month in Nature, Prof Gabriel Waksman, his group member Dr Sebastian Geibel and their collaborators have revealed the structural and energetic process by which bacteria transport pili across their outer membrane. Pili are a key target for a new generation of antibiotics, as without them bacteria are unable to group together and to stick to human cells causing infection.

In the cystitis bacteria, pili enable bacteria to group together and then to attach to the wall of the bladder. The bladder cells then engulf the bacteria and this makes antibiotic treatment very difficult. Once inside the bladder cells the bacteria can lie dormant, making recurrent infections common. It is believed that a new generation of antibiotics could be developed to disrupt the process of pili biogenesis, making the condition easier to treat.

Previous research by the ISMB members uncovered how pili biogenesis is initiated by the protein FimD – an usher in the outer cell wall. FimD is responsible for recruiting subunits, assembling them into a pilus, and secreting the pilus as it is being formed. From this work, the team was able to develop a model for the way the usher carry out all these tasks. The latest research, funded by the Medical Research Council, provides experimental proofs for the model proposed before and shows how, once the subunits have been assembled, the new pilus is secreted from inside the FimD protein to the exterior, via a pore, across the outer bacterial membrane.

The team has now revealed that as the pilus is assembled, the first subunit (FimH) engages with the usher and undergoes structural changes. This creates the necessary energy for this subunit, which forms the tip of the pilus, to displace the plug which is normally found inside the pore, and to pass through the pore itself. As subsequent subunits of the pilus pass into the pore, other structural changes in FimH prevent the pilus retreating back through the pore.
The team has also revealed that within the usher’s pore there are specific binding sites for the tip and the subsequent subunits of the pilus. These binding sites are 180 degrees apart within the barrel of the pore (facing each other); so that the pilus is held in a central position as it emerges from the pore, facilitating its exit.  Furthermore, it has n that as the pilus passes through the pore it follows a rotational and translational path, enabling subsequent subunits to continue being added within the usher as the tip emerges, while the pilus is still held in a central position.

"For the first time we have been able to see the structural and energy pathways via which the FimD usher protein facilitates the transport of the newly assembled pilus across the outer membrane of the bacteria. This process is a key target for the development of new antibiotics, as if biogenesis of new pili can be disrupted the bacteria will be unable to attach themselves to human cells and infection will be much less likely. “We have been working for a number of years to try and understand the process of pili biogenesis and an understanding of this process takes us a step closer to the development of new antibiotics which will successfully treat cystitis – a common and extremely painful condition, as well as other bacterial infections.”

[Posted: April 2013]

 

ISMB's 5th Bi-Annual Retreat - registration now open
April 2013

Registration is open for the 2013 ISMB retreat. The retreat will take place at Robinson College, Cambridge on 3rd and 4th July. For more information and to register, visit the ISMB Retreat webpages.

[Posted: April 2013]

 

Dr Adeline Goulet paper selected as Article of the Month by the French Society of Biochemistry and Molecular Biology

April 2013

A study by Dr Adeline Goulet in the Moores group, “The structural basis of force generation by the mitotic motor kinesin-5”, has recently been published in The Journal of Biological Chemistry (Dec 28 (2012); 287(53): 44654-66.)

Kinesin-5 motors are important in eukaryotes for the formation and maintenance of the microtubule-based, bipolar mitotic spindle. Kinesin-5s have also been of great interest as novel targets for anti-cancer therapies: kinesin-5-specific drugs block mitosis and are in phase II clinical trials. By using cryo-electron microscopy and sub-nanometre resolution structure determination, Goulet et al have visualised ATP-dependent conformational changes in the kinesin-5 motor domain while bound to its microtubule tracks. These structures provide insight into the mechanism of force generation by kinesin-5s. They also present evidence for auto-regulation of motor activity by a kinesin-5-specific loop that acts as a competitive inhibitor to ATP binding. Future work will be directed at understanding the significance of this finding in the context of the mitotic spindle.

The paper has been selected as Article of the month (April) of the Société Française de Biochimie et de Biologie Moléculaire (http://www.sfbbm.fr/index.php?option=com_content&view=category&layout=blog&id=98&Itemid=62). This work is an inter-disciplinary collaboration with Professor Steve Rosenfeld at the Cleveland Clinic, and was funded by the BBSRC.

[Posted: April 2013]

 

Professor Steve Perkins receives MRC, EPSRC-NSF and Alexion grants
April 2013

Congratulations to Prof Steve Perkins, who has been awarded the following grants:

  • MRC grant worth £630,000 over 3 years, funding one PDRA
  • An EPSRC-NSF grant worth £1.4 million over 4 years, funding up to four PDRAs
  • An Alexion grant worth £133,000 over 1 year, funding one PDRA

[Posted: April 2013]

 

Professor Gabriel Waksman receives MRC grant
April 2013

Congratulations to Prof Gabriel Waksman, who has been awarded a MRC grant worth £2,000,000. The grant will fund 3 PDRAs over 5 years.

[Posted: April 2013]

 

ISMB Students in Research Poster Competition
March 2013

On 25th and 26th February, UCL ran a Research Poster Competition which offered graduate students an opportunity to meet, advertise and discuss the innovative research they are undertaking.

Overall 247 students registered for this year's Research Poster Competition (Arts & Humanities, Laws, Social & Historical Sciences – 13; Built Environment, Engineering Sciences, Mathematical & Physical Sciences – 66; Brain Sciences & Life Sciences – 101, and Medical Sciences & Population Health Sciences – 67).

In the Brain Sciences & Life Sciences Group two ISMB students won runner up prizes (£100 each):

Anna Adams, (Kaila Srai Group)
"Exploring New Routes to Labelled Hepcidin"

Susan Andrew, (Richard Hayward Group)
"You are what you eat: host ion scavenging by intracellular Chlamydia trachoma tis"

[Posted: March 2013]

 

Drs Hazel Smith, Andrea Townsend-Nicholson and Suzanne Ruddy receive SLMS Innovation grants

March 2013

Congratulations to Drs Hazel Smith, Andrea Townsend-Nicholson and Suzanne Ruddy on being awarded SLMS Innovation grants. The grants will be used to implement an exciting Chemistry module for Biological Science students; develop interactive online tutorials for Bioscience students and strengthen links with Yale and to produce films that showcase research laboratories to our undergraduate students.

[Posted: March 2013]

 

Welcome to Prof David Lomas

New Dean of Medical Sciences and ISMB Core Member

The ISMB is delighted to welcome as an ISMB member Prof. David Lomas PhD, ScD, FRCP, FMedSci.
David is the new Dean of the Faculty of Medical Sciences at UCL. His research interests are in understanding the mechanisms of diseases caused by protein misfolding, in particular the serpinopathies, in order to develop novel therapies.

David chairs the MRC Population and Systems Medicine Board, the Respiratory Therapy Area Board at GlaxoSmithKline, and is Chair of the Research Committee and Trustee of the British Lung Foundation. More recently he has chaired the strategic priorities working group for the NHS 100,000 genome project. David has strong experience in applying structural, molecular, cell and computational biology techniques to address unmet clinical needs. Such interface work is increasingly important but it can be challenging for clinicians and scientists, who often work in isolation from each other, to bridge successfully. He is very keen to facilitate such cross-talk between researchers in the ISMB and UCL-affiliated clinicians. Examples of this might include arranging access to relevant ex vivo clinical samples to further test hypotheses supported by in vitro data, or discussing relevant clinical applications of a novel technology. David is happy to be contacted with ideas for such interactions (d.lomas@ucl.ac.uk). They fit within his broader strategy whereby UCL’s internationally prestigious hospitals will actively partner with new (and existing) world-class scientific institutes to optimise biomedical research at all levels.

[Posted: March 2013]

 

Professor Gabriel Waksman receives ERC Advanced Grant
February 2013

Congratulations to Professor Gabriel Waksman, who has been awarded a ERC Advanced Grant of just over £2 million for the project, 'Structural biology of Legionella’s Effectors and Secretion System'. The grant will fund 3 PDRAs over 5 years.

[Posted: March 2013]

 

 

 

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