Investigation into the Evolution of a Protein Enzyme from Random Sequence Origin

Project: Research project

Project Details


Intellectual Merit. We are interested in the origins and early evolution of enzyme catalysis. How the first protein enzymes evolved from a primordial pool of random sequences remains a fundamental unanswered question in biology. One possibility is that enzymes, by chance, had some intrinsic catalytic function that was optimized by natural selection. An alternative scenario is that enzymes evolved from proteins that initially only bound their substrates and later adapted to catalyze reactions with those substrates. To address this question, we combine the principles of Darwinian evolution with X-ray crystallography to study the mechanism by which proteins evolve function. Through this process, we discovered a protein from random sequence origin that catalyzes a reaction with the substrate for which it was selected. Based on this observation, we speculate that many enzymes may have originated from proteins that initially only bound their substrates and later acquired the ability to catalyze reactions with those substrates. To our knowledge, this is the first example of a functional enzyme from random sequence origin. The practical value of studying how proteins evolve function is that this knowledge could one day be used to create tailor-made enzymes in the laboratory. In this regard, our approach is ideal for evaluating the amount of information that is needed to specify a polypeptide with a desired functional property and the requirements needed to change or improve an existing function. The focus of this proposal is to investigate the evolutionary path by which our synthetic, nonbiological protein evolved catalytic function. The specific aims for this proposal are: Specific Aim 1: Assemble a complete set of high-resolution co-crystal structures for proteins 18-19, 18-19 (N32D), 18-19 (D65V), and DX with ATP. Specific Aim 2: Develop a detailed understanding of the role the N32D and D65V mutations play in protein catalysis. Specific Aim 3: Examine the variation of sequences identified in the DX selection for a correlation between specific mutations and ATPase activity.
Effective start/end date9/15/088/31/12


  • NSF: Directorate for Biological Sciences (BIO): $405,870.00


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