Structural and functional studies of alpha-N-terminal methylation

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DNA, the recipe of human life, leads to the production of proteins in cells. These proteins then assemble together to form sub-microscopic machineries, necessary to create the miracle of life. Although they are numerically a pretty large number, the number of different genes encoded by our DNA is limited. This restricts, thus, the number of different proteins and their corresponding functions. As a result, evolution has designed a number of special genes in our DNA that leads to the production of special proteins capable of modifying all other proteins in particular ways, leading to an exponential increase in the diversity and dynamics of the entire population of human proteins contributing to the optimal function of human body. My research program at the University of Toronto is dedicated to investigate a unique class of these special protein modifying natural phenomena called -N-terminal methylation, which is literally the addition of a special chemical hat, methyl groups, to one specific end of proteins. Although our current knowledge on the biological functions of this special chemical hat is very little, recent research data suggest that this special chemical hat may play important diverse biological roles in higher living organisms. For example, research evidence suggest that the removal of this special chemical hat-encoding gene from the mouse DNA results in a high mortality rate shortly after birth as well as signs of premature aging and deficient DNA repair abilities, implying the potential involvement of this special chemical hat in human diseases particularly cancer. The key initiative from my research program will use a special technology called X-ray crystallography to visualize how this special chemical hat is added onto other cellular proteins by the special class of protein-modifying human proteins. This initiative will create a foundation on which this previously scientifically under-explored field of -N-terminal methylation, the ubiquitously present natural phenomenon of the addition of the special chemical hat onto human proteins, can expand. The discoveries spearheaded by my research program will not only further strengthen the global leadership position of Canada in biological sciences, but also contribute to the advent of therapeutic agents against human diseases associated with abnormal -N-terminal methylation in the near future, ultimately improving the health of Canadians and people around the world.