title: Coil-to-helix transitions in intrinsically disordered methyl CpG binding protein 2 and its isolated domains.
abstract: Methyl CpG binding protein 2 (MeCP2) is a canonical intrinsically disordered protein (IDP), that is, it lacks stable secondary structure throughout its entire polypeptide chain. Because IDPs often have the propensity to become locally ordered, we tested whether full-length MeCP2 and its constituent domains would gain secondary structure in 2,2,2-trifluoroethanol (TFE), a cosolvent that stabilizes intramolecular hydrogen bonding in proteins. The α-helix, β-strand/turn, and unstructured content were determined as a function of TFE concentration by deconvolution of circular dichroism data. Results indicate that approximately two-thirds of the unstructured residues present in full-length MeCP2 were converted to α-helix in 70% TFE without a change in β-strand/turn. Thus, much of the MeCP2 polypeptide chain undergoes coil-to-helix transitions under conditions that favor intrachain hydrogen bond formation. The unstructured residues of the N-terminal (NTD) and C-terminal (CTD) domains were partially converted to α-helix in 70% TFE. In contrast, the central transcription regulation domain (TRD) became almost completely α-helical in 70% TFE. Unlike the NTD, CTD, and TRD, the unstructured content of the methyl DNA binding domain and the intervening domain did not change with increasing TFE concentration. These results indicate that the coil-to-helix transitions that occur in full-length MeCP2 are localized to the NTD, CTD, and TRD, with the TRD showing the greatest tendency for helix formation. The potential relationships between intrinsic disorder, coil-to-helix transitions, and MeCP2 structure and function are discussed.
authors.affiliation: Department of Biochemistry and Molecular Biology, Campus Delivery 1870, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Kristopher C
authors.initials: KC
authors.lastname: Hite
authors.forename: Anna A
authors.initials: AA
authors.lastname: Kalashnikova
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hansen
mesh_terms: D000818:Animals; D002645:Chickens; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry* / Q000302:isolation & purification; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D014270:Trifluoroethanol / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D051783:Methyl-CpG-Binding Protein 2; D012997:Solvents; D014270:Trifluoroethanol