title: A human transcription factor in search mode.
abstract: Transcription factors (TF) can change shape to bind and recognize DNA, shifting the energy landscape from a weak binding, rapid search mode to a higher affinity recognition mode. However, the mechanism(s) driving this conformational change remains unresolved and in most cases high-resolution structures of the non-specific complexes are unavailable. Here, we investigate the conformational switch of the human mitochondrial transcription termination factor MTERF1, which has a modular, superhelical topology complementary to DNA. Our goal was to characterize the details of the non-specific search mode to complement the crystal structure of the specific binding complex, providing a basis for understanding the recognition mechanism. In the specific complex, MTERF1 binds a significantly distorted and unwound DNA structure, exhibiting a protein conformation incompatible with binding to B-form DNA. In contrast, our simulations of apo MTERF1 revealed significant flexibility, sampling structures with superhelical pitch and radius complementary to the major groove of B-DNA. Docking these structures to B-DNA followed by unrestrained MD simulations led to a stable complex in which MTERF1 was observed to undergo spontaneous diffusion on the DNA. Overall, the data support an MTERF1-DNA binding and recognition mechanism driven by intrinsic dynamics of the MTERF1 superhelical topology.
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hauser
authors.affiliation: Suffolk Community College, Selden, NY 11784, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Essuman
authors.affiliation: Great Neck South High School, Great Neck, NY 11023, USA.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: He
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Coutsias
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia-Diaz
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA carlos.simmerling@stonybrook.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D059371:DNA, B-Form; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D059371:DNA, B-Form; C105178:MTERF1 protein, human; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D004247:DNA