title: Reconstructing Ancient Proteins to Understand the Causes of Structure and Function.
abstract: A central goal in biochemistry is to explain the causes of protein sequence, structure, and function. Mainstream approaches seek to rationalize sequence and structure in terms of their effects on function and to identify function's underlying determinants by comparing related proteins to each other. Although productive, both strategies suffer from intrinsic limitations that have left important aspects of many proteins unexplained. These limits can be overcome by reconstructing ancient proteins, experimentally characterizing their properties, and retracing their evolution through time. This approach has proven to be a powerful means for discovering how historical changes in sequence produced the functions, structures, and other physical/chemical characteristics of modern proteins. It has also illuminated whether protein features evolved because of functional optimization, historical constraint, or blind chance. Here we review recent studies employing ancestral protein reconstruction and show how they have produced new knowledge not only of molecular evolutionary processes but also of the underlying determinants of modern proteins' physical, chemical, and biological properties.
authors.affiliation: Department of Ecology and Evolution, University of Chicago, Illinois 60637; email: ghochberg@uchicago.edu.
authors.forename: Georg K A
authors.initials: GKA
authors.lastname: Hochberg
authors.affiliation: Department of Ecology and Evolution, University of Chicago, Illinois 60637; email: joet1@uchicago.edu.|Department of Human Genetics, University of Chicago, Illinois 60637.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Thornton
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D016782:Apicomplexa / Q000201:enzymology; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D009154:Mutation; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D055503:Protein Multimerization; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D025262:Vacuolar Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; D015800:Protozoan Proteins; D010088:Oxidoreductases; D025262:Vacuolar Proton-Translocating ATPases
keywords: ancestral reconstruction; epistasis; evolutionary biochemistry; historical contingency; vertical analysis