Conserved Helix-flanking Prolines Modulate Intrinsically Disordered Protein:target Affinity by Altering the Lifetime of the Bound Complex
Document Type
Article
Publication Date
2017
Keywords
Chemical Structure, Genetics, Kinetic Parameters, Peptides and Proteins, Screening Assays
Digital Object Identifier (DOI)
https://doi.org/10.1021/acs.biochem.7b00179
Abstract
Appropriate integration of cellular signals requires a delicate balance of ligand–target binding affinities. Increasing the level of residual structure in intrinsically disordered proteins (IDPs), which are overrepresented in these cellular processes, has been shown previously to enhance binding affinities and alter cellular function. Conserved proline residues are commonly found flanking regions of IDPs that become helical upon interacting with a partner protein. Here, we mutate these helix-flanking prolines in p53 and MLL and find opposite effects on binding affinity upon an increase in free IDP helicity. In both cases, changes in affinity were due to alterations in dissociation, not association, rate constants, which is inconsistent with conformational selection mechanisms. We conclude that, contrary to previous suggestions, helix-flanking prolines do not regulate affinity by modulating the rate of complex formation. Instead, they influence binding affinities by controlling the lifetime of the bound complex.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Biochemistry, v. 56, issue 18, p. 2379-2384
Scholar Commons Citation
Crabtree, Michael D.; Borcherds, Wade M.; Poosapati, Anusha; Shammas, Sarah L.; Daughdrill, Gary W.; and Clarke, Jane, "Conserved Helix-flanking Prolines Modulate Intrinsically Disordered Protein:target Affinity by Altering the Lifetime of the Bound Complex" (2017). Molecular Biosciences Faculty Publications. 173.
https://digitalcommons.usf.edu/bcm_facpub/173
