Current post: Professor of Biochemistry, University of Manchester, UK.

Previous posts:

2009 - 2014        Senior Lecturer, Faculty of Life Sciences, University of Manchester.

2007 - 2009        Lecturer, Faculty of Life Sciences, University of Manchester.

2001 - 2007        Royal Society Olga Kennard Research Fellow, Faculty of Life Sciences, University of Manchester.
1998 - 2001        Postdoctoral research associate, School of Biological Sciences, University of Manchester.
1998 - 1998        Royal Society Study Visit, School of Biological Sciences, University of Auckland, New Zealand.
1994 - 1997        BBSRC-CASE PhD Student, University of Sheffield.

The research in my laboratory focuses on the structure and growth factor regulation of extracellular matrix proteins. Many matrix molecules form fibrillar assemblies and the novel application of structural biology and biophysical techniques is revealing exciting insights into their molecular assembly and structural organisation. We are using a range of techniques including small angle X-ray scattering (SAXS), cryo-TEM with single particle analysis and electron tomography to tease out the structural details.

Regulation of growth factor signalling by the extracellular matrix

The bone morphogenetic proteins (BMPs) are powerful growth factors, crucial in maintaining normal tissue structure and function and for essential processes in early embryonic developmental. Large extracellular proteins form inhibitory complexes with these growth factors to regulate their activity. One such regulator, Chordin, acts by binding to BMPs thereby preventing their association with BMP receptors on the cell surface. We have shown that Chordin has a horse-shoe shaped structure that supports BMP-binding in a co-operative manner (Troilo et al., PNAS USA 2014). Twisted gastrulation (Tsg) has both pro- and anti-BMP properties, we showed that both of these properties are mediated by interaction with chordin (Troilo et al., Matrix Biol 2016).

Tolloid proteinases have important roles in tissue assembly and developmental patterning by processing a diverse range of extracellular protein precursors. The tolloid proteinases play an essential role in collagen fibrillogenesis which is necessary for processes such as bone growth. They also release growth factors from inhibitory complexes regulating signalling important for tissue homeostasis and developmental processes. We have shown that dimerisation of mammalian tolloid limits substrate access to the active site, a novel mechanism of internal regulation for controlling binding of substrates (Berry et al., PNAS USA 2009) but there is variability across the tolloid family in dimerisation and substrate specificity (Bayley et al., 2016 Sci Rep; Winstanley et al., 2015 eLife).

Structural analysis of microfibrillar assemblies from elastic tissues

Fibrillin is an elastic fibre protein that has a principal role in the structure and function of organs that require elasticity, such as large arteries, lung and skin. We are analysing whole microfibrillar assemblies, using cryo-TEM and treating the repetitive microfibrillar structure as a string of single particles. With these methods we have identified individual molecules within the microfibril repeat and can describe their molecular organisation. Fibrillin binds to latent TGFβ binding proteins (LTBPs) and we showed that LTBP1 has an extended conformation with stable matrix-binding N-terminus and flexible TGFβ-binding C-terminus. Moreover LTBP1 forms short filament-like structures which is enhanced in the presence of HS and stabilized by transglutaminase-2 cross-links (Troilo et al., Sci Rep 2016).

Elastin enables the reversible deformation of elastic tissues and can withstand decades of repetitive forces. Tropoelastin is the soluble precursor to elastin, the main elastic protein found in mammals. We determined the nanostructure of tropoelastin using X-ray and neutron scattering, allowing us to identify discrete regions of the molecule. Tropoelastin is an asymmetric coil, with a protruding foot that encompasses the C-terminal cell interaction motif (Baldock et al., PNAS USA 2011; Yeo et al., PNAS USA 2012) and has discrete modes of flexibility mediated by a hinge region (Yeo et al., Sci Advances 2016).

Collagen VI has a ubiquitous distribution throughout connective tissues but is particularly enriched close to cells and around basement membranes where it forms a molecular bridge between cells and other matrix components. Mutations in the collagen VI genes give rise to heritable muscular dystrophies. Using combinatorial imaging techniques including cryoEM, electron tomography and serial blockface SEM imaging we have determined the molecular organisation of collagen VI microfibrils and their hierarchical assembly (Godwin et al., Acta Biomaterialia 2016).