title: Correlation of fitness landscapes from three orthologous TIM barrels originates from sequence and structure constraints.
abstract: Sequence divergence of orthologous proteins enables adaptation to environmental stresses and promotes evolution of novel functions. Limits on evolution imposed by constraints on sequence and structure were explored using a model TIM barrel protein, indole-3-glycerol phosphate synthase (IGPS). Fitness effects of point mutations in three phylogenetically divergent IGPS proteins during adaptation to temperature stress were probed by auxotrophic complementation of yeast with prokaryotic, thermophilic IGPS. Analysis of beneficial mutations pointed to an unexpected, long-range allosteric pathway towards the active site of the protein. Significant correlations between the fitness landscapes of distant orthologues implicate both sequence and structure as primary forces in defining the TIM barrel fitness landscape and suggest that fitness landscapes can be translocated in sequence space. Exploration of fitness landscapes in the context of a protein fold provides a strategy for elucidating the sequence-structure-fitness relationships in other common motifs.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Yvonne H
authors.identifier: 0000-0002-3422-8164
authors.initials: YH
authors.lastname: Chan
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Sergey V
authors.identifier: 0000-0002-1507-7460
authors.initials: SV
authors.lastname: Venev
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Konstantin B
authors.initials: KB
authors.lastname: Zeldovich
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: C Robert
authors.initials: CR
authors.lastname: Matthews
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D007209:Indole-3-Glycerol-Phosphate Synthase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D048229:Sulfolobus solfataricus / Q000737:chemistry* / Q000201:enzymology; D013816:Thermodynamics; D020124:Thermotoga maritima / Q000737:chemistry* / Q000201:enzymology; D016963:Thermus thermophilus / Q000737:chemistry* / Q000201:enzymology
chemical_list: D011994:Recombinant Proteins; D007209:Indole-3-Glycerol-Phosphate Synthase