Abstract
The centrality of protein conformation in so many aspects of physiology, as well as the inherent susceptibility to disruption of native structure according to environmental conditions, suggest that misfolding may be a broader feature of human disease than commonly appreciated. The environment of a cancer cell is a challenging one for protein structure and stability. Numerous cellular factors, such as reactive oxygen species, molecular crowding, oncogenic and passenger mutations, and aberrant post-translational modifications all contribute to the destabilization and loss of native structures of numerous proteins expressed in cancer cells. We present a structure-based model that enables us to predict regions of low stability on the surface of a protein, by calculating the free energy for exposure. The result of the calculation reveals an unfolding free energy landscape. These low-stability regions constitute candidate epitopes for anti-body or small molecule therapies. We discuss our predictions for several proteins implicated in cancer, such as EGFR, Fas, PrPc, Notch, CD20, CD44, Her2,Neuropilin and MUC1, and we also discuss the implications of our findings.
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