title: Native-based simulations of the binding interaction between RAP74 and the disordered FCP1 peptide.
abstract: By dephosphorylating the C-terminal domain (CTD) of RNA polymerase II (Pol II), the Transcription Factor IIF (TFIIF)-associating CTD phosphatase (FCP1) performs an essential function in recycling Pol II for subsequent rounds of transcription. The interaction between FCP1 and TFIIF is mediated by the disordered C-terminal tail of FCP1, which folds to form an α-helix upon binding the RAP74 subunit of TFIIF. The present work reports a structure-based simulation study of this interaction between the folded winged-helix domain of RAP74 and the disordered C-terminal tail of FCP1. The comparison of measured and simulated chemical shifts suggests that the FCP1 peptide samples 40-60% of its native helical structure in the unbound disordered ensemble. Free energy calculations suggest that productive binding begins when RAP74 makes hydrophobic contacts with the C-terminal region of the FCP1 peptide. The FCP1 peptide then folds into an amphipathic helix by zipping up the binding interface. The relative plasticity of FCP1 results in a more cooperative binding mechanism, allows for a greater diversity of pathways leading to the bound complex, and may also eliminate the need for "backtracking" from contacts that form out of sequence.
authors: Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors: Sushant
authors: S
authors: Kumar
authors: Scott A
authors: SA
authors: Showalter
authors: William G
authors: WG
authors: Noid
mesh_terms: D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D019473:Transcription Factors, TFII / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D019473:Transcription Factors, TFII; D010749:Phosphoprotein Phosphatases; C056604:transcription factor TFIIF