Professor Sheena Radford

Professor Sheena Radford

Profile

I joined the University of Leeds in 1995 as a Lecturer in the School of Biochemistry and Molecular Biology, progressing to Reader in 1998 and Professor in 2000. In 2009 I became the Deputy Director of the Astbury Centre for Structural Molecular Biology, and its Director in 2012. I also became Astbury Professor of Biophysics in 2014.

Before coming to Leeds, I graduated with a BSc in Biochemistry at the University of Birmingham, completed my PhD in Biochemistry at the University of Cambridge with Professor R.N. Perham, FRS, and held various postdoctoral posts and a Royal Society University Research Fellowship at the Oxford Centre for Molecular Sciences.

I currently supervise about 30 PhD students and postdoctoral researchers in my laboratory. In total, more than 80 PhD students have been, or are being, supervised: many of them are now employed in academic research, 18 have other academic posts, about a third have industrial posts, and others have positions such as technical editing and other roles.  More than 65 post-doctoral research assistants have been or are being supervised; of those who have moved on, about 15% have academic posts, and the majority of others are post-doctoral research in the UK and overseas.

I have published more than 320 peer-reviewed papers and have given more than 400 invited lectures at national and international conferences in countries including the UK, Germany, Denmark, USA, Australia, Japan, Sweden, Ireland, Belgium, Switzerland, Greece, Spain, Italy, France, The Netherlands, Portugal, Croatia, Israel, Austria, Canada, and Thailand.

In the last five years I have served, or am serving on, 6 major research funding panels, 12 Scientific Advisory Boards at prestigious institutions and I have served on editorial boards for several journals, and am currently Associate Editor of the Journal of Molecular Biology.

I have been awarded several prizes and awards, including the 1996 Biochemical Society Colworth Medal, the 2005 Royal Society of Chemistry Astra-Zeneca prize in Proteins and Peptides, the 2009 Hites Award from the American Society for Mass Spectrometry (joint with Professor Alison Ashcroft), the Protein Society Carl Branden award in 2013, and the 2015 Rita and John Cornforth Award of the Royal Society of Chemistry (also jointly with Professor Alison Ashcroft). I was elected member of EMBO in 2007, member of Academia Europeae in 2020, Fellow of the Academy of Medical Sciences in 2010, the Royal Society in 2014, and was delighted to be made honorary member of the British Biophysical Society in 2014, a Fellow of the Biophysical Society in 2018, and an Officer of the Most Excellent Oder of the British Empire (OBE) in 2020 for services to molecular biology research. In January 2021 I received a Royal Society Professorship.

My research is focused on fundamental structural molecular biology, specifically in the measurement of the conformational dynamics of proteins and the elucidation of the role that these motions play in protein folding and misfolding of both water-soluble and membrane proteins. Using a wide range of biophysical methods and combining these with protein chemistry, molecular biology, chemical biology and structural biology, my research focus over the last 30 years has been the delineation of the mechanisms by which proteins fold or misfold; how dynamic excursions enable proteins to self-associate into amyloid fibrils - the complex macromolecular assemblies associated with some of the deadliest human diseases; and how proteins fold into the bacterial outer membranes of Gram-negative organisms.

My major research achievements to date have included the use of native mass spectrometry, NMR and single molecule methods to characterise the intermediates in protein folding and in amyloid formation; to identify and delineate the mechanisms of action of small molecules able to interrupt protein aggregation, and the discovery of how and why different protein-protein interactions propagate amyloid formation whilst others inhibit assembly. In parallel, we have been using our biophysical toolkit of methods to understand how Gram-negative outer membrane proteins (OMPs) fold, how folding is supported by ATP-independent chaperones in the periplasm and how the β-barrel assembly machinery (BAM) catalyses OMP folding and assembly into the bacterial cell envelope.

Links which may be of interest (links to online lectures are under Research Interests)

https://www.youtube.com/watch?v=r1eK3DLCMcM , a lecture to celebrate being elected a Fellow of the Royal Society, 14 November 2014: Folding proteins – from Astbury to Amyloid and Ageing

https://www.youtube.com/watch?v=_lRQeGstRgo, Navigating a Career in Science (as a woman), 6 November 2017: presented at the University of Malta

 

Responsibilities

  • Astbury Professor of Biophysics and Royal Society Professor
  • Director of the Astbury Centre for Structural Molecular Biology
  • Group Leader of the Radford Laboratory

Research interests

Research interests

One of the most fascinating questions in biology is how proteins are able to fold from their linear amino acid sequence and assemble into complex, functional entities given just the information provided by the amino acid sequence. A related and equally important facet of the same fundamental question is how protein misfolding can lead to protein aggregation, cellular dysfunction and disease. These issues are the major focus of my research and are tackled using a broad range of techniques including protein chemistry, structural molecular biology, chemical biology, cell biology and biophysical methods.

The folding question became even more fascinating because of the discovery that folding in the cell is assisted by chaperone proteins, and that misfolding events in vivo are responsible for several diseases. Maintaining drug stability for protein biologics represents a major challenge to the pharmaceutical industry, as highlighted by the transport and storage challenges posed by some of the new COVID-19 vaccines. We are using our knowledge of protein folding and aggregation to try to assist in the design on more aggregation-resistant protein drugs.

Current projects include:

  • Mechanism(s) of protein mis-folding and assembly into amyloid
  • Outer membrane protein (OMP) folding mechanisms, and role of chaperones and the β-barrel membrane (BAM) machinery in OMP folding
  • Stabilising proteins of therapeutic and industrial interest against aggregation
  • Method development (MS, NMR, single molecule and biophysical methods)

Detailed research programme:

1. Mechanism(s) of protein mis-folding and assembly into amyloid

1.	Mechanism(s) of protein misfolding and assembly into amyloid

How and why proteins aggregate into amyloid are important fundamental questions that have far-reaching biomedical importance. Focusing on the proteins (β2-microglobulin (dialysis related amyloidosis); amylin (type II diabetes); α-synuclein (Parkinson’s) and Aβ (Alzheimer’s), work in the group aims to map the structural mechanism of amyloid formation and to develop reagents to control aggregation in vitro and in vivo. Recent highlights include structure determination of oligomers by NMR (Karamanos (2019) eLife) and fibrils by cryoEM (with Ranson) (Iadanza (2018) Nature Comms.); discovery of small molecules that modulate amyloid formation by ESI-MS (Young (2015) Nature Chem.; and demonstration that early protein-protein interactions in amyloid formation are specific and can be targeted to arrest assembly in vitro and in vivo (Doherty (2020) Nature Struct. Mol. Biol.).

Some of our recent manuscripts in this area, including those cited above, are listed here:

Screening and classifying small molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. Young, L.M., Saunders, J.C., Mahood, R.A., Revill, C.H., Foster R.J., Tu, L.-H., Raleigh, D.P., Radford, S.E. & Ashcroft, A.E. (2015) Nature Chemistry, 7, 1, 73-81, doi: 10.1038/nchem.2129 

The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism. Iadanza, M.G., Silvers, R., Boardman, J., Smith, H.I., Karamanos, T.K., Debelouchina, G.T., Su, Y., Griffin, R.G., Ranson, N.A., & Radford, S.E. (2018) Nature Comms, 9, 4517 – 4527, doi: 10.1038/s41467-018-06761-6

Structural mapping of oligomeric intermediates in an amyloid assembly pathway. Karamanos, T.K., Jackson, M.P., Calabrese, A.N., Goodchild, S.C., Cawood, E.E., Thompson, G.S., Kalverda, A.P., Hewitt, E.W., & Radford, S.E. (2019) eLife, 8, e46574, doi: 10.7554/eLife.46574.001 

A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function. Doherty, C.P.A., Ulamec, S.M., Maya-Martinez, R., Good, S.C., Makepeace, J., Khan, G.N., van Oosten-Hawle, P., Radford, S.E. & Brockwell, D.J. (2020) Nat. Struct. Mol. Biol., 27, 249-259, doi: 10.1038/s41594-020-0384-x

Amyloid structures: Much more than just a cross-β fold. Gallardo, R., Ranson, N.A. & Radford, S.E. (2020) Curr. Op. Struct. Biol, 60, 7-16, doi: 10.1016/j.sbi.2019.09.001

Collagen I weakly interacts with the β-sheets of β2-microglobulin and enhances conformational exchange to induce amyloid formation. Hoop, C.L., Zhu, J., Bhattacharya, S., Tobita, C.A., Radford, S.E. & Baum, J. (2020) JACS, 142, 1321-1331, doi: 10.1021/jacs.9b10421

The role of the IT state in D76N β2-microglobulin aggregation: a crucial intermediate or an innocuous bystander? Smith, H.S., Guthertz, N., Cawood, E., Maya-Martinez, R., Breeze, A., Radford, S.E. (2020) J. Biol. Chem, 295, 12474-12484, doi10.1074/jbc.ra120.014901

Fibril structures of diabetes-related amylin variants reveal a basis for surface templated assembly.  Gallardo, R., Iadanza, M.G., Xu, Y., Heath, G.R., Foster, R., Radford, S.E. & Ranson, N.A. (2020) Nature Struct. Mol. Biol., 27, 1048-1056, doi: 10.1038/s41594-020-0496-3

Looking beyond the core: The role of flanking regions in the aggregation of amyloidogenic peptides and proteins. Ulamec, S.M., David J. Brockwell, D.J. & Radford, S.E. (2020) Frontiers in NeuroSci., 14, 611285, doi: 10.3389/fnins.2020.611285

Modulation of amyloidogenic protein self-assembly using tethered small molecules.  Cawood, E.E., Ebo, J.S., Karamanos, T.K., Radford, S.E. & Wilson, A.E. (2020) JACS, 142, 20845-20854, doi: 10.1021/jacs.0c10629

Visualizing and trapping transient oligomers in amyloid assembly pathways. Cawood, E.E., Karamanos, T.K., Wilson,  A.J. & Radford, S.E. (2021) Biophys. Chem., 268, 106505, doi: 10.1016/j.bpc.2020.106505

2.  Outer membrane protein (OMP) folding mechanisms, and the role of chaperones and the β-barrel membrane (BAM) machinery complex

2.	Outer membrane protein (OMP) folding mechanisms, and the role of chaperones and the β-barrel membrane (BAM) machinery complex

How OMPs fold and assemble into the asymmetric outer-membrane (OM) of Gram-negative bacteria is a second research theme in our laboratory. In a collaborative multidisciplinary team (with David Brockwell, Neil Ranson, Roman Tuma and Ian Collinson (Bristol)) we are investigating how OMPs cross the inner-membrane via SecYEG (Fessl (2018) eLife)); traverse the periplasm aided by chaperones (Skp/SurA) (Schiffrin (2016) Nature SMB, Calabrese (2020) Nature Comms), fold into membranes in vitro (Huysmans (2010) PNAS) and in vivo catalysed by the essential β-barrel membrane machinery (BAM) (Iadanza (2016) Nature Comms, Schiffrin (2017) JMB). Building on these insights we are currently exploring the dynamic motions of BAM during catalysis and how this can be harnessed to generate new antibacterial agents against Gram-negative pathogens.

Some of our recent manuscripts in this area (including those cited above) are listed here:

The transition state for the folding of an outer membrane protein. Huysmans, G.H.M., Baldwin, S.A., Brockwell, D.J. & Radford, S.E. (2010) Proc. Natl. Acad. Sci USA, 107, 4099-4104, doi: 10.1073/pnas.0911904107

Skp is a multivalent chaperone of outer membrane proteins. Schiffrin, R., Calabrese, A.N., Devine, P.W.A., Harris, S.A., Ashcroft, A.E., Brockwell, D.J. & Radford, S.E. (2016) Nat. Struct. Mol. Biol, 23, 786-793, doi: 10.1038/nsmb.3266

Lateral opening in the intact β-barrel assembly machinery captured by cryo-EM. Iadanza, M.G., Higgins, A.J., Schiffrin, R., Calabrese, A.N., Brockwell, D.J., Ashcroft, A.E., Radford, S.E. & Ranson, N.A. (2016) Nature Comms, 7, 12865, doi: 10.1038/ncomms12865

Effects of periplasmic chaperones and membrane thickness on BamA-catalysed outer membrane protein folding.  Schiffrin, B., Calabrese, A.N., Higgins, A.J., Humes, J.R., Ashcroft, A.E., Kalli, A.C., Brockwell, D.J. & Radford, S.E. (2017) J. Mol. Biol, 429, 3776-3792, doi: 10.1016/j.jmb.2017.09.008

Dynamic action of the Sec machinery during initiation, protein translocation and termination. Fessl, T., Watkins, D., Oatley, P., Allen, W.J., Corey, R.A., Horne, J., Baldwin, A., Radford, S.E., Collinson, I. & Tuma, R. (2018) eLife, 7, e35112, doi: 10.7554/eLife.35112

Inter-domain dynamics in the chaperone SurA permit multi-site binding to its outer membrane protein clients. Calabrese, A.N., Schiffrin, B., Watson, M., Karamanos, T.K., Walko, M., Humes, J.R., Horne, J.E., White, P., Wilson, A.J., Kalli, A.C., Tuma, R., Ashcroft, A.E., Brockwell, D.J & Radford, S.E. (2020) Nat. Comms, 11, 2155, doi: 10.1038/s41467-020-15702-1

Structural insight into the formation of lipoprotein-β-barrel complexes by the β-barrel assembly machinery. Létoquart, J., Rodriguez-Alonso, R., Nguyen, S., Louis, G., Calabrese, A.N., Radford, S.E., Seung Hyun Cho, S.H., Remaut, H., & Collet, J.F. (2020) Nature Chem. Biol,. 16, 1019-1025, doi: 10.1101/823146

Role of the lipid bilayer in outer membrane protein folding. Horne, J.E., Brockwell, D.J & Radford, S.E. (2020). J. Biol. Chem., 295, 10340-10367, doi: 10.1074/jbc.REV120.011473

Distortion of the bilayer and dynamics of the BAM complex in lipid nanodiscs. Iadanza, M.G., Schiffrin, B., White, P., Watson, M.A., Horne, J.E., Higgins, A.J., Calabrese, A.N., Brockwell, D.J., Tuma, R., Kalli, A.C., Radford, S.E. & Ranson, N.A. (2020) Communication Biol., 3, 766, doi: 10.1038/s42003-020-01419-w

3. Stabilising proteins of therapeutic and industrial interest against aggregation 

Stabilising proteins of therapeutic and industrial interest against aggregation

We are also exploiting our knowledge of protein folding/aggregation to practical benefit by screening amyloidogenic proteins, as well as proteins of interest to biopharma, for hotspots that cause aggregation. By coupling aggregation to bacterial growth using a tripartite β-lactamase fusion construct, we have discovered small molecules that prevent aggregation of amyloidogenic proteins (Saunders (2016) Nature Chem. Biol.). With David Brockwell and our collaborators in AstraZeneca, we recently combined the assay with directed evolution to enhance the resilience of biopharmaceutically-relevant antibodies to aggregation (Ebo (2020) Nature Comms.). Finally, in collaboration with David Brockwell and Nik Kapur (Mechanical Engineering, Leeds), we are examining how flow fields enhance, or cause, aggregation by flow-induced protein deformations (Dobson (2017) PNAS, Willis (2020) Eng. Rep.).

Some of our recent manuscripts in this area (including those cited above) are listed here:

An in vivo platform for identifying inhibitors of protein aggregation.  Saunders, J.C., Young, L.M., Mahood, R.A., Revill, C.H., Foster, R.J., Jackson, M.P., Smith, D.A.M., Ashcroft, A.E., Brockwell, D.J. & Radford, S.E. (2016) Nature Chem. Biol, 12, 94-101, doi: 10.1038/nchembio.1988

Inducing protein aggregation by extensional flow.  Dobson, J., Kumar, A., Willis, L.F., Tuma, R., Higazi, D.R., Turner, R., Lowe, D.C., Ashcroft, A.E., Radford, S.E., Kapur, N. & Brockwell, D.J. (2017) Proc. Nat Acad. Sci. USA, 114, 4673-4678, doi: 10.1073/pnas.1702724114

An in vivo platform to select and evolve aggregation-resistant protein therapeutics.  Ebo, J.S., Saunders, J.C., Devine, P.W.A., Gordon, A.M., Warwick, A.S., Schiffrin, B., Chin, S., England, E., Button, J.D., Lloyd, C., Bond, N., Ashcroft, A.E., Radford, S.E., Lowe, D.C., Brockwell, D.J. (2020) Nat. Comms, 11, 1816, doi: 10.1038/s41467-020-15667-1

Using protein engineering to understand and modulate aggregation. Ebo, Jessica S., Guthertz, Nicolas, Radford, Sheena E. & Brockwell, David J. (2020) Curr. Op. Struct. Biol., 60, 157–166, doi: 10.1016/j.sbi.2020.01.005

The uniqueness of flow in probing the aggregation behavior of clinically-relevant antibodies. Willis, L.F., Kumar, A., Jain, T., Caffry, I., Xu, Y., Radford, S.E., Kapur, N., Vasquez, M. & Brockwell, D.J. (2020) Eng. Rep.2,  e12147, doi: 10.1002/eng2.12147

4. Method development (MS, NMR, single molecule and biophysical methods) 

Method development (MS, NMR, single molecule, biophysical methods

Major developments in methods and instrumentation have played a key role in increasing in our understanding of protein structure, function and folding. Future developments in these fields will also require innovative approaches that cross the boundaries between disciplines. We have been involved in many exciting collaborations to fulfil this aim. Building on a longstanding collaboration with Alison Ashcroft (now Emeritus), and now with Frank Sobott and Andrew Wilson we are developing and expanding our arsenal of methods to interrogate protein folding, protein-protein interactions and protein complexes, including MS methods (HDX-MS and fast photochemical oxidation of proteins (FPOP-MS)) (Cornwell (2018) J. Am. Soc. MS, Cornwell (2019) Analyt. Chem.); ion mobility MS to map oligomers formed during aggregation (Young (2017) Chem. Sci.) and ligand binding to amyloid precursors (Young (2015) Nature Chem.) and rapid crosslinking to map protein-chaperone interactions (Horne (2018) Angewandte Chemie, Calabrese (2020) Nature Comms). We have also developed nanoinjection (with Paolo Actis, Pollard Institute, School of Electronic and Electrical Engineering) to introduce defined numbers of protein molecules into cells (Chau and Actis, Nanoletters, 2020). Developments in NMR methods remain a mainstay of our laboratory activities, whilst, in collaboration with David Brockwell we are involved in exciting developments in the use of the AFM and flow devices for measurements of protein unfolding and protein binding.

Some of our recent manuscripts in this area (including those cited above) are listed here:

Screening and classifying small molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. Young, L.M., Saunders, J.C., Mahood, R.A., Revill, C.H., Foster R.J., Tu, L.-H., Raleigh, D.P., Radford, S.E. & Ashcroft, A.E. (2015) Nature Chemistry, 7, 1, 73-81, doi10.1038/nchem.2129

Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers.  Young, L.M., Tu, L.H., Raleigh, D.P., Ashcroft, A.E. & Radford, S.E. (2017) Chem. Sci, 8, 5030-5040, doi: 10.1039/c7sc00620a

Rapid mapping of protein interactions using tag-transfer photocrosslinkers. Horne, J.E., Walko, M., Calabrese, A.N., Levenstein, M.A., Brockwell, D.J., Kapur, N., Wilson, A.J. & Radford, S.E. (2018) Angew. Chemie, 57, 16688-16692, doi: 10.1002/anie.201809149 

Comparing hydrogen deuterium exchange and fast photochemical oxidation of proteins: A structural characterisation of wild-type and ΔN6 β2-microglobulin. Cornwell, O., Radford, S.E., Ashcroft, A.E. Ault, J.R. (2018) JASMS, 29, 2413-2426, doi: 10.1007/s13361-018-2067-y 

Long-range conformational changes in monoclonal antibodies revealed using FPOP-LC-MS/MS. Cornwell, O., Bond, N.J., Radford, S.E. & Ashcroft, A.E. (2019) Anal Chem, 91, 15163-15170, doi: 10.1021/acs.analchem.9b03958 

Inter-domain dynamics in the chaperone SurA permit multi-site binding to its outer membrane protein clients. Calabrese, A.N., Schiffrin, B., Watson, M., Karamanos, T.K., Walko, M., Humes, J.R., Horne, J.E., White, P., Wilson, A.J., Kalli, A.C., Tuma, R., Ashcroft, A.E., Brockwell, D.J & Radford, S.E. (2020) Nat. Comms, 11, 2155, doi: 10.1038/s41467-020-15702-1 

PyXlinkViewer: a flexible tool for visualisation of protein chemical crosslinking data within the PyMOL molecular graphics system. Schiffrin, B., Radford, S.E., Brockwell, D.J. & Calabrese, A.N. (2020) Protein Sci., 29, 1851-1857, doi: 10.1002/pro.3902

Macromolecular crowding enhances the detection of DNA and proteins by a solid-state nanopore. Chau, C.C., Radford, S.E., Hewitt, E.W. & Actis, P. (2020) Nanoletters, 20, 5553-5561, doi: 10.1021/acs.nanolett.0c02246

For further details about the Radford laboratory, people involved, molecular images and available opportunities please see:  

Astbury website:

https://astbury.leeds.ac.uk

Personal web page on Astbury website:

Professor Sheena Radford OBE, FMedSci, FRS (Director) : The Astbury Centre for Structural Molecular Biology (leeds.ac.uk)

Information about the Radford Research groups:

http://sheena-radford-lab.uk/radford.php

Other useful information:

Links to videos about specific projects: 

Online seminar for the series on Protein Folding and Dynamics for Weizmann Institute, Israel, 18 May 2020: Early Steps in Amyloid Assembly: The Achilles Heel of a Disease Mechanism: https://www.youtube.com/watch?v=I1ehplDAmXs

Online seminar for the Proteostasis Consortium series, 4 November 2020: Early Steps in Amyloid Assembly: The Achilles Heel of a Disease Mechanism: https://www.proteostasisconsortium.com/seminars/

A lecture to celebrate being elected a Fellow of the Royal Society, 14 November 2014: Folding proteins – from Astbury to Amyloid and Ageing: https://www.youtube.com/watch?v=r1eK3DLCMcM

Recent press articles:

Yorkshire Post article about Royal Society Professorial Fellowship: https://www.yorkshirepost.co.uk/education/leeds-scientist-backed-royal-society-transform-our-understanding-alzheimers-parkinsons-and-nature-memory-3101007

https://www.yorkshirepost.co.uk/news/ill-never-stop-dancing-says-leeds-biophysicist-professor-sheena-radford-who-hopes-dispel-stereotypes-183917

Other links which may be of interest:

https://en.wikipedia.org/wiki/Sheena_Radford 

Sheena Radford, OBE, FRS, FMedSci, MAE | LinkedIn

<h4>Research projects</h4> <p>Any research projects I'm currently working on will be listed below. Our list of all <a href="https://biologicalsciences.leeds.ac.uk/dir/research-projects">research projects</a> allows you to view and search the full list of projects in the faculty.</p>

Qualifications

  • BSc, Birmingham, 1984
  • PhD, Cambridge, 1987

Professional memberships

  • Order of the British Empire (OBE), 2020
  • Member of the Academia Europaea, 2020
  • Honorary Fellow, St John’s College, Cambridge, 2019
  • Fellow of the Biophysical Society for leadership in protein biophysics, 2017
  • Fellow of the Royal Society, 2014
  • Honorary Member of the British Biophysical Society, 2014
  • Fellow of Academy of Medical Sciences, 2010
  • Fellow of the European Molecular Biology Organization (EMBO), 2007
  • Fellow of the Royal Society of Chemistry, 2003
  • Member of the Biochemical Society and the Protein Society, ongoing

Student education

I have taught Biochemistry at both undergraduate and postgraduate levels at the University of Leeds since 1995, and been an active tutor and supervisor of students at all levels. I currently teach basic mechanisms and concepts in protein folding, and contribute to Advanced Topic Units to final year students. Our laboratory also hosts students for their final year research projects (Biochemistry and Biological Sciences) for both BSc and MBiol schemes.

Research groups and institutes

  • Structural Biology

Current postgraduate researchers

<h4>Postgraduate research opportunities</h4> <p>We welcome enquiries from motivated and qualified applicants from all around the world who are interested in PhD study. Our <a href="https://phd.leeds.ac.uk">research opportunities</a> allow you to search for projects and scholarships.</p>