Transcription factors (TF) can switch between two DNA-binding modes – a search mode that facilitates TF sliding along DNA and a recognition mode for high affinity binding. The mechanism(s) that drive the switch are not well understood since experimental structures are in short supply. In this talk, we investigate how the mitochondrial transcription terminator MTERF1 switches into search mode. MTERF1 is a modular TF with a helical topology that tracks the major groove of DNA. With a crystal structure in hand, our goal was to characterize the search mode structure and dynamics of MTERF1 prior to recognition. The crystal structure shows MTERF1 binds unwound DNA with three flipped bases once recognition has occurred. Our simulations on the other hand evince a highly dynamic picture of apo MTERF1 in which the protein freely adopts new conformations whose helical parameters – pitch and radius – are a match for the major groove of normal B-DNA. These low pitch apo MTERF1 structures were docked to B-DNA and simulated with standard MD. The complex was stable and we discovered that MTERF1 spontaneously began sliding along the major groove of the B-form DNA. Our simulations support a recognition mechanism driven by MTERF1 helical dynamics.

Human transcription factor in search mode

251st National Meeting (2016)

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