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Proteins are the workhorses of the cell, carrying out a variety of biological activities from signaling to catalysis. The structure or architecture of a protein, also known as its fold, is the scaffold upon which these functions are mounted. It is thought that there are several thousand different types of protein fold in nature, of which many hundreds are known today through the work of structural biologists.
Central to our work is the question of how evolution produced so many distinct protein architectures. There is presently very little experimental evidence germane to this question, as very few mutations have been shown to significantly alter protein structures. However, my work on the Arc repressor protein at MIT has shown that in some cases very simple genetic mutations are capable of radically changing a protein's fold.
We now intend to study the mechanisms by which the evolution of fold actually occurs in nature. Our approach is, first, to identify families of proteins which share a common ancestor but which do not share a common fold. Then, through structural and bioinformatic analysis, to reconstruct the evolutionary process which led to the different structures. We will also use protein design, protein engineering and random mutation experiments to mimic structural evolution in the laboratory.