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Experimental support for the foldability-function tradeoff hypothesis

Title: Experimental support for the foldability-function tradeoff hypothesis: segregation of the folding nucleus and functional regions in fibroblast growth factor-1.
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Name(s): Longo, Liam, author
Lee, Jihun, author
Blaber, Michael, author
Type of Resource: text
Genre: journal article
text
Date Issued: 2012-12-01
Physical Form: computer
Physical Form: online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_23047594 (IID), 10.1002/pro.2175 (DOI), PMC3575920 (PMCID), 23047594 (RID), 23047594 (EID)
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575920.
Subject(s): Fibroblast Growth Factor 1/chemistry
Humans
Models, Molecular
Protein Conformation
Protein Denaturation
Protein Folding
Thermodynamics
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_23047594
Owner Institution: FSU
Is Part Of: Protein science : a publication of the Protein Society.
1469-896X
Issue: iss. 12, vol. 21

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Longo, L., Lee, J., & Blaber, M. (2012). Experimental support for the foldability-function tradeoff hypothesis: segregation of the folding nucleus and functional regions in fibroblast growth factor-1. Protein Science : A Publication Of The Protein Society. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_23047594