title: Experimental support for the foldability-function tradeoff hypothesis: segregation of the folding nucleus and functional regions in fibroblast growth factor-1.
abstract: The acquisition of function is often associated with destabilizing mutations, giving rise to the stability-function tradeoff hypothesis. To test whether function is also accommodated at the expense of foldability, fibroblast growth factor-1 (FGF-1) was subjected to a comprehensive φ-value analysis at each of the 11 turn regions. FGF-1, a β-trefoil fold, represents an excellent model system with which to evaluate the influence of function on foldability: because of its threefold symmetric structure, analysis of FGF-1 allows for direct comparisons between symmetry-related regions of the protein that are associated with function to those that are not; thus, a structural basis for regions of foldability can potentially be identified. The resulting φ-value distribution of FGF-1 is highly polarized, with the majority of positions described as either folded-like or denatured-like in the folding transition state. Regions important for folding are shown to be asymmetrically distributed within the protein architecture; furthermore, regions associated with function (i.e., heparin-binding affinity and receptor-binding affinity) are localized to regions of the protein that fold after barrier crossing (late in the folding pathway). These results provide experimental support for the foldability-function tradeoff hypothesis in the evolution of FGF-1. Notably, the results identify the potential for folding redundancy in symmetric protein architecture with important implications for protein evolution and design.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306-4300, USA.
authors.forename: Liam
authors.initials: L
authors.lastname: Longo
authors.forename: Jihun
authors.initials: J
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Blaber
mesh_terms: D016220:Fibroblast Growth Factor 1 / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D016220:Fibroblast Growth Factor 1