2006
DOI: 10.1002/prot.21227
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Relative tolerance of mesostable and thermostable protein homologs to extensive mutation

Abstract: Evolvability, designability, and plasticity of a protein are properties that are important to protein engineers, but difficult to quantify. Here, we directly compare homologous AroQ chorismate mutases from the thermophile Methanococcus jannaschii and the mesophile Escherichia coli with respect to their capacity to accommodate extensive mutation. The N-terminal helix comprising about 40% of these proteins was randomized at the genetic level using a binary pattern of hydrophobic and hydrophilic residues based on… Show more

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Cited by 67 publications
(59 citation statements)
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“…A cytochrome P450 enzyme that had been engineered to contain a handful of stabilizing mutations was nearly twice as tolerant to random mutations (25). And a thermostable chorismate mutase was a remarkable 10-fold more tolerant to randomization of a large helical region than its mesostable counterpart (35). The extensive stability-mediated epistasis suggested by these experiments can be visualized in terms of a protein stability threshold, as illustrated in Fig.…”
Section: Much Of the Epistatic Coupling Between Mutations Is Simply Ementioning
confidence: 90%
“…A cytochrome P450 enzyme that had been engineered to contain a handful of stabilizing mutations was nearly twice as tolerant to random mutations (25). And a thermostable chorismate mutase was a remarkable 10-fold more tolerant to randomization of a large helical region than its mesostable counterpart (35). The extensive stability-mediated epistasis suggested by these experiments can be visualized in terms of a protein stability threshold, as illustrated in Fig.…”
Section: Much Of the Epistatic Coupling Between Mutations Is Simply Ementioning
confidence: 90%
“…For example, the AroQ corismate mutase from the thermophile Methanococcus janaschii tolerates ~10-fold more mutations relative to its E. coli counterpart (Loeb et al, 1989). Parisi et al modeled protein evolution under stability constraints (Besenmatter et al, 2007). At each step, this sequential in silico model introduced mutations and selected against structural perturbation.…”
Section: D) Thermodynamic Stability Is Limiting For Evolutionmentioning
confidence: 99%
“…Enzymatic stability considerations should become key for protein engineering. Consensus design based on phylogenetic comparison has already been used to improve enzyme stability (Forrer et al, 2004;Ng & Henikoff, 2006) and thermostable enzymes will likely be chosen as templates in preference to their mesophile counterparts in future directed evolution experiments because of their increased evolvability (Besenmatter et al, 2007;Watanabe et al, 2006).…”
mentioning
confidence: 99%
“…In fact, high inter-residue contact density has been shown to correlate with increased rates of sequence evolution in yeast proteins (17); a large number of buried residues imparts robustness, enhancing the evolvability of solvent-exposed residues. Predictions that extra stability allows a protein to accept a wider range of mutations while maintaining its native structure have been borne out in selection experiments with enzymes like cytochrome P450 (18) and chorismate mutase (19). Because stable proteins from thermophilic organisms tolerate a greater number of destabilizing mutations than their mesophilic counterparts, they are often preferred as starting points for enzyme design projects.…”
mentioning
confidence: 99%