Native-based simulations of the binding interaction between RAP74 and the disordered FCP1 peptide

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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.

Original languageEnglish (US)
Pages (from-to)3074-3085
Number of pages12
JournalJournal of Physical Chemistry B
Volume117
Issue number11
DOIs
StatePublished - Mar 21 2013

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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