title: The spatial architecture of protein function and adaptation.
abstract: Statistical analysis of protein evolution suggests a design for natural proteins in which sparse networks of coevolving amino acids (termed sectors) comprise the essence of three-dimensional structure and function. However, proteins are also subject to pressures deriving from the dynamics of the evolutionary process itself--the ability to tolerate mutation and to be adaptive to changing selection pressures. To understand the relationship of the sector architecture to these properties, we developed a high-throughput quantitative method for a comprehensive single-mutation study in which every position is substituted individually to every other amino acid. Using a PDZ domain (PSD95(pdz3)) model system, we show that sector positions are functionally sensitive to mutation, whereas non-sector positions are more tolerant to substitution. In addition, we find that adaptation to a new binding specificity initiates exclusively through variation within sector residues. A combination of just two sector mutations located near and away from the ligand-binding site suffices to switch the binding specificity of PSD95(pdz3) quantitatively towards a class-switching ligand. The localization of functional constraint and adaptive variation within the sector has important implications for understanding and engineering proteins.
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: McLaughlin
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Poelwijk
authors.forename: Arjun
authors.initials: A
authors.lastname: Raman
authors.forename: Walraj S
authors.initials: WS
authors.lastname: Gosal
authors.forename: Rama
authors.initials: R
authors.lastname: Ranganathan
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D019143:Evolution, Molecular; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D054731:PDZ Domains / Q000235:genetics* / Q000502:physiology*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D050505:Mutant Proteins; D011506:Proteins