Clair Baldock, BSc PhD
Matrix protein structure

The research in my laboratory focuses on the structure and growth factor regulation of extracellular matrix (ECM) proteins. Many ECM molecules undergo polymerisation to form fibrillar assemblies, 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. Extracellular regulation of BMPs is of therapeutic interest in relation to a broad range of pathologies including cancer, vascular disease and arthritis. Large extracellular proteins form inhibitory complexes with these growth factors, thereby preventing receptor activation. One such regulator, Chordin, acts by binding to BMPs thereby preventing their association with BMP receptors on the cell surface. We have recently shown that Chordin has a horse-shoe shaped structure that supports BMP-binding in a co-operative manner (Troilo et al., PNAS USA 2014).

Tolloid proteinases have important roles in tissue assembly and developmental patterning, two fundamental processes in mammalian biology. They process 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).

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. Using SAXS and TEM, a very compact region of the molecule has been identified that was previously thought to be rigid and rod-like, significantly this region contains the binding motifs for integrins and heparan sulphate. At the next level of hierarchy,we are analysing whole microfibrillar assemblies, using cryo-TEM and treating the repetitive microfibrillar structure as a string of single particles.With these new methods we have identified individual molecules within the microfibril repeat and have described their organisation in a concertina fashion which reveals a mode of extension.

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 small angle 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).

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.The goal of this research is to define the molecular organisation of collagen VI microfibrils (Beecher et al., 2011).

Recent discoveries

Recent key publications

Yeo, G.C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L.B., Wise, S.G., Matthews, J., Mithieux, S.M. and Weiss, A.S.(2012). The tropoelastin bridge region positions the cell-interactive Cterminus and contributes to elastic fiber assembly. Proc Natl Acad Sci U S A. 109, 2878-2883. PubMed

Baldock, C., Oberhauser, A.F., Ma, L., Lammie, D., Siegler, V., Mithieux, S.M., Tu, Y., Yuen Ho Chow, J., Suleman, F., Malfois, M., Rogers, S., Guo, L., Irving, T.C., Wess, T.J., & Weiss, A.S. (2011). Shape of tropoelastin, the highly-extensible protein that controls human tissue elasticity. PNAS USA. 108:4322-7.. PubMed link

Berry, R., Jowitt, T. A., Ferrand, J., Roessle, M., Grossmann, J. G., Canty-Laird, E. G., Kammerer, R. A., Kadler, K. E., and Baldock, C. (2009) Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid, Proc Natl Acad Sci U S A. 106, 8561-6 PubMed link.

 

Full list of publications