Project Details

Description

The Emergence of Protein Folds The Emergence of Protein Folds The Emergence of Protein Folds Modern proteins evolved from a small number of primordial folds, but it is not known how these molecules evolved into complex structures capable of supporting life on Earth. One could imagine that protein evolution proceeded through a series of discrete chemical steps in which random pools of sequences gave rise to relatively simple protein folds that were initially quite small (<100 amino acid residues), but over time recombined in various ways to adopt larger structures that were better equipped to support the needs of a primordial metabolism. Understanding the evolutionary pathway that allowed simple protein folds to evolve into larger, more complex structures is a grand challenge in evolutionary biology. We hypothesize that early protein folds (proto-proteins) with simple domain structures nucleated the evolution of diverse protein structures by stabilizing the folding of larger proteins. This hypothesis suggests that the total structural diversity that we observe today in nature may have originated from a small number of distinct protoprotein folds. We recently explored this possibility by evolving a small (80-amino acid) de novo generated ATP-binding protein into a new size-expanded protein of 160 amino acids. This technological advance, which is a major leap forward in de novo protein evolution, yielded numerous sequences, suggesting that many distinct solutions exist to the problem of how a small protein fold can be expanded into a much larger protein domain. While the architecture of these proteins is not yet known, we have identified at least one protein that is monomeric and adopts a discrete fold after expression and purification in Escherichia coli. Given the large number of sequences that remain in the pool, we plan to test our hypothesis by examining the level of structural diversity that can emerge from a model proto-protein system. We propose to evaluate the diversity of protein architectures that can emerge from a model proto-protein. To achieve this goal, we propose the following specific aims: Specific Aim 1: Solve the three-dimensional structure of DX-19.3 a model protoprotein created by de novo protein evolution. Specific Aim 2: Expand our pool of model proto-proteins by de novo evolution. Specific Aim 3: Characterize the structural diversity of the pool of proto-proteins. The results from this proposed research are expected to yield insight into the origin and evolution of proteins on the primitive Earth and help generate experimental information concerning the possible emergence of life elsewhere in the universe.
StatusFinished
Effective start/end date6/10/149/30/15

Funding

  • NASA: Goddard Space Flight Center: $197,234.00

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