... understanding life in molecular detail

Prof Neil Ranson

Electron microscopy, macromolecular assembly, structure, viruses, folding, OMPs

I am interested in the structures of large macromolecular assemblies, and particularly in how conformational change in such structures drives biological function. We use cryo-electron microscopy, cryo-electron tomography and computational image processing methods to determine the structures of such complexes in 3-D. Current research interests are focussed around the assembly, structure and function of RNA & DNA viruses, the structure of amyloid protein in vitro and in vivo, and the folding of outer membrane proteins into the outer membrane of Gram negative bacteria.

Current major projects include:
  • Understanding virus structure and genome packaging
  • Virus receptor binding and conformational change
  • The folding & maturation of OMPs via the BAM complex
  • The structure of amyloid aggregates and the basis of cytotoxicity

Figure 1. Cryo-EM image of bacteriophage MS2 bound to its receptor, the bacterial F-pilus. The right-hand side of the image has been false-coloured to show the pilus (purple), with bound MS2 (red), together with the small fraction of MS2 that lack a viral maturation protein and therefore do not bind (green).

Single-stranded (ss)RNA viruses are major pathogens across all kingdoms of life, and new viruses of this type continue to emerge because of factors such as climate change, population growth and increased mobility. These viruses present society with huge public health and economic challenges, but few therapeutic options exist beyond vaccination, which is not always practical or effective. We need new therapies capable of tackling the diseases these viruses cause, and to develop them we need a deeper understanding of all aspects of the ssRNA virus lifecycle.

Figure 2. Asymmetric structure of MS2 bound to its receptor. The fitted atomic coordinates are shown on the left hand side. The dashed lines illustrates that the virus binds at a slight (9°) angle on the pilus (Dent et al, 2013).

We are interested in several aspects of virus lifecycles. Firstly we want to understand how viruses infect their host cells. This type of virus typically has an icosahedrally symmetric protein shell to protect its genome, but they also typically have asymmetric features as well, such as infectivity or maturation proteins, not to mention the genome itself. Such features are vital for the virus’ lifecycle, but we understand them poorly because they are lost when symmetry averaging is applied during structure determination. We are developing biochemical, methodological and computational approaches to allow asymmetric structure determination of this type of virus.

Figure 3. A section through the 9Å cryo-EM structure of MS2. The EM map has been masked away in the protein shell region. The remaining density corresponds to the encapsidated genomic RNA (Toropova et al, 2008).

One such approach is to look at the complex a virus makes with its receptor. This is especially important because it is the first step in establishing a new infection. It also leads directly to a large, highly charged RNA molecule crossing a membrane bilayer to get into the cytoplasm of a cell where it can be replicated and translated, and this process is very poorly understood. We are interested in all aspects of

receptor binding and in understanding the molecular details of how a genomic RNA enters the cell.

The assembly pathways of ssRNA viruses, and the structures of packaged RNAs that they lead to, are candidates for anti-viral therapy: if we understand how assembly is driven perhaps we can block it, if we know the structure a packaged RNA must adopt perhaps we can stop it.

We are also interested in protein misfolding and aggregation. The deposition of proteins as amyloid aggregates is linked to a wide range of diseases, such as Alzheimer’s and Parkinson’s diseases, and dialysis related amyloidosis. We want to understand the structure of the amyloid aggregates themselves, and the molecular mechanisms that underpin aggregation. We also want to understand how the process of aggregation into amyloid leads to the toxicity that can have such a devastating effects. To do this we are imaging the effects that amyloid aggregates have on cells and biological membranes.

Detailed research programme                  Close ▲

Professor of Structural Molecular Biology
BSc (Bristol) PhD (Bristol)

PDRA, Birkbeck College London, 1997-2002
University Research Fellow, University of Leeds, 2002-2008
Lecturer, University of Leeds, 2008-2012

Astbury Building, Room 8.108
School of Molecular and Cellular Biology
0113 343 7065

Selected Publications

  1. Iadanza, M.G.*, Silvers, R.*, Boardman, J., Smith, H., Karamanos, T., Griffin, R.G.‡, Ranson, N.A.‡ and Radford, S.E.‡. (2018). The cryo-EM structure of a b-2-microglobulin fibril shows the molecular basis of a common amyloid architecture. Nature Communications, DOI:10.1038/s41467-018-06761-6

  2. Hesketh, E.L.‡, Saunders, K.‡, Fisher, C., Potze, J., Stanley, J., Lomonossoff, G.P.‡ & Ranson, N.A.‡ (2018). How to build a geminate virus capsid. Nature Communications, 9, 2369. DOI:10.1038/s41467-018-04793-6

  3. Patel, N.*, White, S.J*., Thompson, R.F., Weiß, E.U., Bingham, R., Zlotnick, A., Dykeman, E., Twarock, R.,‡ Ranson, N.A.‡ & Stockley, P.G.‡ (2017). The HBV RNA pregenome encodes specific interactions with the viral core protein that can promote nucleocapsid assembly. Nature Micro., DOI:10.1038/ nmicrobiol.2017.98

  4. Iadanza, M.G., Higgins, A.J., Schiffrin, B., Calabrese, A.N., Brockwell, D.J., Ashcroft, A.E., Radford, S.E.‡ & Ranson, N.A.‡ (2016) Lateral opening in the intactβ-barrel assembly machinery captured by cryo-EM. Nature Comms.DOI:10.1038/ncomms1286