title: Structural divergence is more extensive than sequence divergence for a family of intrinsically disordered proteins.
abstract: The p53 transactivation domain (p53TAD) is an intrinsically disordered protein (IDP) domain that undergoes coupled folding and binding when interacting with partner proteins like the E3 ligase, MDM2, and the 70 kDa subunit of replication protein A, RPA70. The secondary structure and dynamics of six closely related mammalian homologues of p53TAD were investigated using nuclear magnetic resonance (NMR) spectroscopy. Differences in both transient secondary structure and backbone dynamics were observed for the homologues. Many of these differences were localized to the binding sites for MDM2 and RPA70. The amount of transient helical secondary structure observed for the MDM2 binding site was lower for the dog and mouse homologues, compared with human, and the amount of transient helical secondary structure observed for the RPA70 binding site was higher for guinea pig and rabbit, compared with human. Differences in the amount of transient helical secondary structure observed for the MDM2 binding site were directly related to amino acid substitutions occurring on the solvent exposed side of the amphipathic helix that forms during the p53TAD/MDM2 interaction. Differences in the amount of transient helical secondary structure were not as easily explained for the RPA70 binding site because of its extensive sequence divergence. Clustering analysis shows that the divergence in the transient secondary structure of the p53TAD homologues exceeds the amino acid sequence divergence. In contrast, strong correlations were observed between the backbone dynamics of the homologues and the sequence identity matrix, suggesting that the dynamic behavior of IDPs is a conserved evolutionary feature.
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 3720 Spectrum Blvd., Suite 321, Tampa, Florida, 33612; The Center for Drug Discovery and Innovation, University of South Florida, 3720 Spectrum Blvd., Suite 321, Tampa, Florida, 33612.
authors.forename: Wade
authors.initials: W
authors.lastname: Borcherds
authors.forename: Stepan
authors.initials: S
authors.lastname: Kashtanov
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wu
authors.forename: Gary W
authors.initials: GW
authors.lastname: Daughdrill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016000:Cluster Analysis; D004285:Dogs; D019143:Evolution, Molecular; D006168:Guinea Pigs; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011817:Rabbits; D016415:Sequence Alignment; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry
chemical_list: D064267:Intrinsically Disordered Proteins; D016159:Tumor Suppressor Protein p53
keywords: intrinsically disordered proteins; protein dynamics; structural divergence; structural evolution