With the advent of high throughput biomolecular engineering techniques, it has become possible to isolate short peptides that bind to a variety of targets ranging from inorganic materials to proteins. The application of peptides as therapeutics has been hampered by the inherent susceptibility of peptides to proteases present throughout the human body. One strategy to overcome this protease susceptibility is to fortify peptides via cyclization or other conformational constraints. Indeed, nature uses this strategy in several classes of peptides such as cyclotides and defensins which are stabilized by networks of disulfide bonds and in some cases head-to-tail cyclization. My group studies a class of peptides termed lasso peptides because of their remarkable slipknot-like structure. This highly entropically disfavored fold endows the peptides with tremendous stability; some lasso peptides retain their structure and function even after boiling in 8 M urea. Lasso peptides are also resistant to proteolysis by digestive proteases such as pepsin and chymotrypsin. In this talk I will describe our efforts in understanding the biosynthesis of lasso peptides with a particular focus on the role of the leader peptide in lasso peptide biosynthesis. Insights into lasso peptide biosynthesis have enabled us to develop a new genome mining approach to discover new lasso peptides. Finally I will describe new work on the catabolism of lasso peptides which provides us with clues about the function of this amazing class of natural products.
A. James (Jamie) Link graduated from Princeton in 2000 with a BSE in chemical engineering. He then pursued a PhD in chemical engineering as an NSF graduate fellow in David Tirrell’s lab at Caltech studying the incorporation of unnatural amino acids into proteins. Between 2005 and 2007 he was an NIH fellow in George Georgiou’s lab at the University of Texas, Austin. In fall 2007, Jamie returned to Princeton to start his own lab in the Department of Chemical and Biological Engineering, where he is now associate professor. His work at Princeton has been recognized with awards including an NSF CAREER grant, a DuPont Young Professorship, and a Sloan Research Fellowship in chemistry.
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