Fellow

Steve Chamberlin

Education

• BS in Chemistry with Computer Science. University of Southampton, UK (1987)
• PhD in Computational Chemistry. University of Southampton, UK (1991)
• MBA in Entrepreneurship. University of Florida, Gainesville, FL (2004)
• Postdoctoral Fellow. CRC Medical Oncology Unit, Southampton, UK (1991)
• Director of Bioinformatics. EraGen Biosciences, Madison, WI (1997)

Research summary

My work exploits my interests in combining computational/modelling approaches with biology, chemistry and physics to learn about the world around us. Research applications of this philosophy are applied in two ways: to better understand experimental data and to guide further work according to predictions of the models we use.

The recent additions of whole genome sequences for several vertebrates is providing a remarkable opportunity to examine the evolution of higher organisms in detail. My current focus is to organize this information with data from different scientific disciplines such as molecular and structural biology, bioinformatics, and chemistry to provide a highly integrated historical representation of the evolution of life on earth. Such detailed databases create several opportunities. They allow us to:

1. sharply question what we know about the underlying evolutionary models that we use on a day-to-day basis
2. create new models that help us to understand the process and mechanics of life more clearly

This fundamental research is supported by test cases and applications that apply these models to scientific questions surrounding human health. These include outbreaks of infectious diseases (SARS), generating tools to predict the functional consequences of single nucleotide polymorphisms (Cystic Fibrosis), and the molecular evolution and natural history of placental mammals in response to changing environments (prostate development and hypertension sensitivity).

Selected Publications

Solution structure of the mEGF/TGF alpha(44-50) chimeric growth factor
Chamberlin, SG Brennan, L Puddicombe, SM Davies, DE Turner, DL
Euro. J. Biochem. 268 (23) 6247-6255 (2001)
<Abstract>

The solution structure of the growth factor chimera mEGF/TGF alpha (44-50) has been determined using an extended version of the DYANA procedure for calculating structures from NMR data. The backbone fold and preferred orientation of the domains of the chimera are similar to those found in previous studies of EGF structures, and several H-bonds used as input constraints in those studies were found independently in the chimera. This shows that the modified activity of the chimera does not result from a major structural change. However, the improved precision of the structure presented here allows the origin of some unusual chemical shifts found in all of these compounds to be explained, as well as the results obtained from some site-specific mutants. Further studies of the properties of this chimeric growth factor should help to elucidate the mechanism(s) of hetero- and homodimerization of the c-erbB receptors.

Functional inferences from reconstructed evolutionary biology involving rectified databases. An evolutionarily-grounded approach to functional genomics.
Benner, SA Chamberlin, SG Liberles, DA Govindarajan, S Knecht, L
Res. MicroBiol. 151 (2) 97-106 (2000)
<Abstract>

If bioinformatics tools are constructed to reproduce the natural, evolutionary history of the biosphere, they offer powerful approaches to some of the most difficult tasks in genomics, including the organization and retrieval of sequence data, the updating of massive genomic databases, the detection of database error, the assignment of introns, the prediction of protein conformation from protein sequences, the detection of distant homologs, the assignment of function to open reading frames, the identification of biochemical pathways from genomic data, and the construction of a comprehensive model correlating the history of biomolecules with the history of planet Earth.

A unified model of c-erbB receptor homo- and heterodimerisation
Chamberlin, SG Davies, DE
Biochim. Biophys. Acta 1384 (2) 223-232 (1998)
<Abstract>

The c-erbB receptor tyrosine kinase family plays an important role in cell regulation. Receptor activation proceeds by the formation of receptor homo- and/or hetero-dimers and is promoted by the binding of a cognate ligand at the cell surface. While some experimental work has demonstrated that the formation of heterodimers can influence a cellular response, the extent of heterodimerisation has not been accurately assessed: the assortment of receptors and ligands gives rise to a complex combinatorial system for which intuitive prediction of homo- and hetero-dimerisation is difficult. We present a mathematical model which combines observations for homo-dimerisation with the additional interactions arising from the presence of multiple c-erbB receptors. We provide a simple explanation for the apparently conflicting results for binding studies carried out with either solubilised receptors, vesicles or cells and our model predicts binding behaviour which is compatible with published experimental findings for cells expressing either one or two c-erbB receptors. This model establishes the basis for interpretation of ligand binding experiments, where variations in the apparent ligand affinity can be attributed to changes in receptor expression or ligand preferences according to the binding profile. (C) 1998 Elsevier Science B.V. All rights reserved.

Structure-function studies of ligand-induced epidermal growth factor receptor dimerization
Neelam, B Richter, A Chamberlin, SG Puddicombe, SM Wood, L Murray, MB Nandagopal, K Niyogi, SK Davies, DE
Biochemistry 37 (14) 4884-4891 (1998)
<Abstract>

We present a novel 96-well assay which we have applied to a structure-function study of epidermal growth factor receptor dimerization. The basis of the assay lies in the increased probability of EGFRs being captured as dimers by a bivalent antibody when they are immobilized in the presence of a cognate ligand. Once immobilized, the antibody acts as a tether, retaining the receptor in its dimeric state with a resultant 5-7-fold increase in binding of a radiolabeled ligand probe. When the assay was applied to members of the EGF ligand family, murine EGF, transforming growth factor alpha, and heparin-binding EGF-like growth factor were comparable with human EGF (EC50 = 2nM); betacellulin, which has a broader receptor specificity, was slightly less effective. In contrast, amphiregulin (AR(1-84)), which has a truncated C-tail and lacks a conserved leucine residue, was ineffective unless used at >1 mu M. We further probed the involvement of the C-tail and the conserved leucine residue in receptor dimerization by comparing the activities of two genetically modified EGFs (the chimera mEGF/TGF alpha(44-50) and the EGF point mutant L47A) and a C-terminally extended form of AR (AR(1-90)) with those of two other unrelated EGF mutants (I23T and L15A). The potency of these ligands was in the order EGF > I23T > mEGF/TGF alpha(44-50) > L47A = L15A much greater than AR(1-90) > AR(1-84). Although AR was much worse than predicted from its affinity, this defect could be partially rectified by co-localization of the immobilizing antibody with heparin. Thus, it seems likely that AR cannot dimerize the EGFR unless other accessory molecules are present to stabilize its functional association with the EGFR.

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