Paula da Fonseca
Structure and function of cell regulatory protein complexes
In all living cells homeostasis, growth and division are critically regulated by highly specialised large multi-subunit protein complexes. Disruptions in these regulatory complexes result in cell malfunctioning and are frequently implicated in diseases such as cancer. The full understanding of the organisation and function of such macromolecular assemblies requires accurate structural information to define the interactions and mechanisms of their component subunits, and how these are integrated within the whole complex.
We study the structure of large macromolecular complexes by electron microscopy and single particle analysis. The interpretation of the resulting three-dimensional maps may be achieved by comparing the structure of the whole complex with that of sub-complexes and/or individual component subunits and by exploiting other biochemical and/or biophysical data. This type of approach is exemplified by studies on the 26S proteasome and the anaphase‑promoting complex, both involved in the ubiquitin/proteasome pathway. As well as defining the structural organisation of macromolecular complexes, single particle analysis can also provide relevant functional information by the analysis of complexes in different functional states, resulting in structures that can be combined as snap-shots of the complex in action.
- da Fonseca, P.C.A., He, J., Morris, E.P. (2012)
Molecular model of the human 26S proteasome.
Mol. Cell 46: 54-66
- da Fonseca, P.C.A., Kong, E.H., Zhang, Z., Schreiber, A., Williams, M.A., Morris, E.P., Barford, D. (2011)
Structures of APC/CCdh1 with substrates identify Cdh1 and Apc10 as the D-box co‑receptor.
Nature 470: 274-278
- Schreiber, A., Stengel, F., Zhang, Z., Enchev, R.I., Kong, E., Morris, E.P., Robinson, C.V., da Fonseca, P.C.A., Barford, D. (2011)
Structural basis for the subunit assembly of the anaphase-promoting complex.
Nature 470: 227-232
- Alice Clark
- David Nicholson