FEBS Biomolecular complexes and assemblies

A FEBS Journal Symposium to honor Richard Perham

Tuesday 2 September

9:00 - 11:00, Room 243


Sheena E. Radford
University of Leeds, UK

Rare Events, Yet Increasing Opportunities: Towards Combatting Amyloid Disease

Most proteins fold efficiently to their native structures in vivo, assisted by molecular chaperones. It is widely known, however, that proteins do misfold and that misfolding events can result in conformational disease. Work in our laboratory aims to elucidate the mechanisms by which proteins fold, or misfold and aggregate. Our aim is to understand the fundamental principles that govern the search of the polypeptide for the native state and to inform the development of therapeutics against misfolding disease. In the lecture I will describe our recent results which have provided new insights into why this protein is amyloidogenic, and how biomolecular collisions between different protein sequences can either turn an initially innocuous protein into an amyloidogenic state, or inhibit the progress of assembly. In addition, I will present data that compare the structure and stability of homo- and hetero-polymeric fibrils formed from related proteins. These findings demonstrate how co-polymerization of related precursor sequences can expand the repertoire of structural and thermodynamic polymorphism in amyloid fibrils, to an extent that is greater than that obtained by polymerization of a single precursor alone.

(1) A diversity of assembly mechanisms of a generic amyloid fold. Eichner, T. & Radford, S.E. (2011) Molecular Cell, 43, 8-18
(2) Expanding the repertoire of amyloid polymorphs by co-polymerization of related protein precursors. Sarell, C.J., Woods, L.A., Su, Y., Debelouchina, G.T., Ashcroft, A.E., Griffin, R.G., Stockley, P.G. & Radford, S.E. (2013) J. Biol. Chem., 288, 7327-7337
(3) Visualization of transient protein-protein interactions that promote or inhibit amyloid assembly. Karamanos, T.K., Kalverda, A.P., Thompson, G.S. & Radford S.E. (2014) Mol Cell, in press


Sheena graduated in Biochemistry at Birmingham, completed her PhD at Cambridge under the supervision of Professor Richard Perham, and then carried out extensive research at Oxford before becoming a lecturer at the University of Leeds in 1995. She became a Reader in 1998, a Professor in 2000, Deputy Director of Astbury Centre for Structural Molecular Biology in 2009, and its Director in 2012. She has run a large and successful research laboratory at the University of Leeds, and is now the Astbury Chair of Biophysics.

Her research is focused on fundamental structural molecular biology, specifically the measurement of the conformational dynamics of proteins and the elucidation of the role that these motions play in protein folding and misfolding in health and disease. Working on both soluble and membrane proteins, she and her group are using a wide range of biophysical methods (including NMR, mass spectrometry and single molecule methods), combined with other approaches spanning molecular dynamics simulation to cellular biology, to determine how proteins fold in all-atom detail; the mechanisms by which proteins misfold; how dynamic excursions enable proteins to self-associate into amyloid fibrils; and the complex macromolecular assemblies associated with some of the deadliest human diseases. They are now exploiting the fundamental insights gained to develop new strategies and routes towards combatting diseases associated with rare conformational states of proteins. She is a Fellow of the Royal Society of Chemistry and of the Academy of Medical Sciences. Her prizes include the Biochemical Society Colworth Medal in 1996 and the Protein Society Carl Branden Award in 2013. She has published more than 200 peer-reviewed papers and has spoken at 127 invited lectures at national meetings and seminars, and 162 invited lectures at international conferences in 20 countries.


Frédéric Dardel, FR

RNA & RNA-protein complexes

Abstract to follow


Biography to follow


Wolfgang Baumeister
Max-Planck-Institute of Biochemistry, Martinsried, DE

Structural studies of the 26S proteasome holocomplex

The 26S proteasome operates at the executive end of the ubiquitin-proteasome pathway for the controlled degradation of intracellular proteins. While the structure of its 20S core particle (CP) has been determined by X-ray crystallography, the structure of the 19S regulatory particle (RP), which recruits substrates, unfolds them, and translocates them to the CP for degradation, has remained elusive. Here, we describe the molecular architecture of the 26S holocomplex determined by an integrative approach based on data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Recently, based on a 6Å structure of the Saccharomyces cerevisiae proteasome, and molecular dynamics-based flexible fitting we were able to present an atomic model of the 26 holocomplex, and we defined ist conformational landscape.


Wolfgang Baumeister studied biology, chemistry and physics at the Universities of Münster and Bonn, Germany, and he obtained his Ph.D. from the University of Düsseldorf in 1973. From 1973-1980 he was Research Associate in the Department of Biophysics at the University of Düsseldorf. He held a Heisenberg Fellowship spending time at the Cavendish Laboratory in Cambridge, England. In 1982 he became a Group Leader at the Max-Planck-Institute of Biochemistry in Martinsried, Germany and in 1988 Director and Head of the Department of Structural Biology. He is also an Honorary Professor on the Physics Faculty at the Technical University in Munich.

Wolfgang Baumeister made seminal contributions to our understanding of the structure and function of the cellular machinery of protein degradation, in particular the proteasome. Moreover, he pioneered the development of cryo-electron tomography. His contributions to science were recognized by numerous awards including the Otto Warburg Medal, the Schleiden Medal, the Louis-Jeantet Prize for Medicine, the Stein and Moore Award, the Harvey Prize in Science and Technology and the Ernst Schering Prize. He is a member of several academies including the US National Academy of Sciences and the American Academy of Arts and Sciences.


Angela Gronenborn
Department of Structural Biology and Pittsburgh Center for HIV- Protein Interaction, University of Pittsburgh School of Medicine, Pittsburgh, US

Synergy between NMR, cryo-EM and large-scale MD simulations - Novel Findings for HIV Capsid Function

Mature HIV-1 particles contain a conical-shaped capsid that encloses the viral RNA genome and performs essential functions in the virus life cycle. Previous structural analysis of two- and three-dimensional arrays provided a molecular model of the capsid protein (CA) hexamer and revealed three interfaces in the lattice. Using the high-resolution NMR structure of the CA C-terminal domain (CTD) dimer and in particular the unique interface identified, it was possible to reconstruct a model for a tubular assembly of CA protein that fit extremely well into the cryoEM density map. A novel CTD-CTD interface at the local three-fold axis in the cryoEM map was confirmed by mutagenesis to be essential for function. More recently, the cryo-EM structure of the tube was solved at 8Å resolution and this cryo-EM structure allowed unambiguous modeling and refinement by large-scale molecular dynamics (MD) simulation, resulting in all-atom models for the hexamer-of-hexamer and pentamer-of-hexamer elements of spheroidal capsids. Furthermore, the 3D structure of a native HIV-1 core was determined by cryo-electron tomography (Cryo-ET), which in combination with MD simulations permitted the construction of a realistic all-atom model for the entire capsid, based on the 3D authentic core structure.


Dr. Gronenborn received Ph.D. in Chemistry from the University of Cologne, Germany. After post-doctoral work with Jim Feeney at The National Institute for Medical Research in Mill Hill, London, UK she continued her research at NIMR in the Division of Physical Biochemistry. In 1984 she moved to the Max Planck Institute of Biochemistry in Martinsried, Germany, as head of the biological NMR group. From 1988 to 2005 she worked at the National Institutes of Health in Bethesda, USA and since 2005 she is a Professor at the University of Pittsburgh Medical School where she currently holds the UPMC Rosalind Franklin Chair in Structural Biology.


Vladimir Uversky
Department of Molecular Medicine, University of South Florida, Tampa, US

Intrinsically disordered proteins: Dancing protein clouds

Intrinsically disordered proteins (IDPs) are biologically active proteins that lack stable structure under physiological conditions and often resemble 'protein clouds'. They are highly abundant in nature and possess very broad functional repertoire, being commonly involved in regulation, signaling, and control pathways where they frequently serve as hubs. Functions of IDPs may arise from the specific disorder form, from inter-conversion of disordered forms, or from transitions between disordered and ordered or ordered and disordered conformations. Functions of IDPs are controlled by alternative splicing and posttranslational modifications. IDPs are tightly controlled under the normal conditions. Dysregulation and dysfunction of IDPs are associated with such human diseases as cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, diabetes and others. Pathogenic IDPs, such as α-synuclein, tau protein, p53, BRCA1 and many other disease-associated disordered hubs are attractive targets for drugs modulating protein-protein interactions. Several strategies have been elaborated for elucidating the mechanisms of blocking of intrinsic disorder-based protein-protein interactions. However, challenges remain in the field of drug development for 'protein clouds'; such development is still in its earliest stage.


Vladimir UVERSKY obtained his Ph.D. in biophysics from Moscow Institute of Physics and Technology (1991) and D.Sc. in biophysics from Institute of Experimental and Theoretical Biophysics, Russian Academy of Sciences (1998). He spent early career working on protein folding at Institute of Protein Research and the Institute for Biological Instrumentation (Russian Academy of Sciences). In 1998, he moved to the University of California Santa Cruz to work on protein folding, misfolding, and protein intrinsic disorder. In 2004, he moved to the Center for Computational Biology and Bioinformatics at the Indiana University Purdue University Indianapolis to work on the intrinsically disordered proteins. Since 2010, he is with the Department of Molecular Biology at the University of South Florida.


David Nicholson
Publishing Director for Life Sciences at Wiley, UK

David Nicholson will give a brief overview of the impact and influence of FEBS Journal on the biochemistry and molecular biology communities under the editorship of Professor Richard Perham of the University of Cambridge. Professor Perham became the Editor of the journal in 1996 and passed the baton to Professor Seamus Martin at the end of 2013. During the his time as Editor, Professor Perham steered the journal through a successful transition from the European Journal of Biochemistry and to the FEBS Journal, whilst also navigating significant change in the environment for scholarly communication.


David Nicholson joined Wiley in 2004 and has over 20 years of experience of working in scientific publishing, largely in editorial and business development roles. David leads Wiley’s journal portfolio in life and earth sciences, working with key partners including FEBS and EMBO, and works with an excellent team of colleagues based in Europe, North America and Asia.