Year: 2015
Type: article
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.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkv1091
Authors: Kevin Hauser, Bernard Essuman, Yiqing He, Evangelos Coutsias, Miguel Garcia-Diaz, Carlos Simmerling
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Awards: Mechanisms of mitochondrial transcription, SBU Chemistry-Biology Interface Training Program, G2240969977, BioPREP: Biology Partnership in Research and Education Program, SUNY LSAMP 2009 Bridge to the Doctorate (BD) Cohort at Stony Brook, The Stony Brook-Brookhaven AGEP Frontiers of Research and Academic Models of Excellence (FRAME) Alliance for Transformation, New Solvent Models, Sampling Methods and Maintenance of Amber Software, New Mathematical Methods for Protein Loop Modeling, Modeling the mechanism of MTERF1-DNA binding and recognition, G7085071097, PRAC - Hierarchical molecular dynamics sampling for assessing pathways and free energies of RNA catalysis, ligand binding, and conformational change, G8606945270
OpenAlex ID: W2222663910