title: Evolution of a Protein Interaction Domain Family by Tuning Conformational Flexibility.
abstract: Conformational flexibility allows proteins to adopt multiple functionally important conformations but can also lead to nonfunctional structures. We analyzed the dynamic behavior of the enzyme guanylate kinase as it evolved into the GK protein interaction domain (GKPID) to investigate the role of flexibility in the evolution of new protein functions. We found that the ancestral enzyme is very flexible, allowing it to adopt open conformations that can bind nucleotide and closed ones that enable catalysis of phosphotransfer from ATP to GMP. Historical mutations that converted the GK from an enzyme to a protein interaction domain dramatically reduce flexibility, predominantly by inhibiting rotations of the protein backbone that are coupled to the global closing motion. Removing flexibility prevents adoption of conformations that cannot fit the protein partner in the binding site. Our results highlight the importance of mutations that optimize protein conformational flexibility with function during evolution.
authors: Department of Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States.
authors: Dustin S
authors: DS
authors: Whitney
authors: Department of Biochemistry, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States.
authors: Brian F
authors: BF
authors: Volkman
authors: Department of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403, United States.
authors: Kenneth E
authors: KE
authors: Prehoda
mesh_terms: D051528:Guanylate Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs
chemical_list: D051528:Guanylate Kinases