title: Modular evolution and the origins of symmetry: reconstruction of a three-fold symmetric globular protein.
abstract: The high frequency of internal structural symmetry in common protein folds is presumed to reflect their evolutionary origins from the repetition and fusion of ancient peptide modules, but little is known about the primary sequence and physical determinants of this process. Unexpectedly, a sequence and structural analysis of symmetric subdomain modules within an abundant and ancient globular fold, the β-trefoil, reveals that modular evolution is not simply a relic of the ancient past, but is an ongoing and recurring mechanism for regenerating symmetry, having occurred independently in numerous existing β-trefoil proteins. We performed a computational reconstruction of a β-trefoil subdomain module and repeated it to form a newly three-fold symmetric globular protein, ThreeFoil. In addition to its near perfect structural identity between symmetric modules, ThreeFoil is highly soluble, performs multivalent carbohydrate binding, and has remarkably high thermal stability. These findings have far-reaching implications for understanding the evolution and design of proteins via subdomain modules.
authors.affiliation: Guelph-Waterloo Centre for Graduate Studies in Chemistry and Biochemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Aron
authors.initials: A
authors.lastname: Broom
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Doxey
authors.forename: Yuri D
authors.initials: YD
authors.lastname: Lobsanov
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Berthin
authors.forename: David R
authors.initials: DR
authors.lastname: Rose
authors.forename: P Lynne
authors.initials: PL
authors.lastname: Howell
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: McConkey
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Meiering
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D017422:Sequence Analysis, DNA
chemical_list: D011506:Proteins