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Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation

Ngo, Huu B. and Lovely, Geoffrey A. and Phillips, Rob and Chan, David C. (2014) Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nature Communications, 5 (1). Art. No. 3077. ISSN 2041-1723. PMCID PMC3936014. doi:10.1038/ncomms4077.

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TFAM (transcription factor A, mitochondrial) is a DNA-binding protein that activates transcription at the two major promoters of mitochondrial DNA (mtDNA)—the light strand promoter (LSP) and the heavy strand promoter 1 (HSP1). Equally important, it coats and packages the mitochondrial genome. TFAM has been shown to impose a U-turn on LSP DNA; however, whether this distortion is relevant at other sites is unknown. Here we present crystal structures of TFAM bound to HSP1 and to nonspecific DNA. In both, TFAM similarly distorts the DNA into a U-turn. Yet, TFAM binds to HSP1 in the opposite orientation from LSP explaining why transcription from LSP requires DNA bending, whereas transcription at HSP1 does not. Moreover, the crystal structures reveal dimerization of DNA-bound TFAM. This dimerization is dispensable for DNA bending and transcriptional activation but is important in DNA compaction. We propose that TFAM dimerization enhances mitochondrial DNA compaction by promoting looping of the DNA.

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Phillips, Rob0000-0003-3082-2809
Chan, David C.0000-0002-0191-2154
Additional Information:© 2014 Macmillan Publishers Limited. Received 31 Jul 2013. Accepted 6 Dec 2013. Published 17 Jan 2014. We are grateful to the Gordon and Betty Moore Foundation and the Sanofi-Aventis Bioengineering Research Program at Caltech for their generous support of the Molecular Observatory at Caltech. Portions of this research were carried out at the Stanford Synchrotron Radiation Lightsource, supported by the US NIH and DOE. We thank Shou-ou Shan (California Institute of Technology) for use of equipment and insightful discussions, and Jens T. Kaiser for helpful discussions about structure determination. This work was supported by NIH grants RO1 GM062967 (D.C.C.), DP1 OD000217A (Directors Pioneer Award, R.P.) and R01 GM085286 (R.P.).
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Sanofi-Aventis Bioengineering Research ProgramUNSPECIFIED
Caltech Molecular ObservatoryUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
NIHRO1 GM062967
NIHDP1 OD000217A
NIHR01 GM085286
Issue or Number:1
PubMed Central ID:PMC3936014
Record Number:CaltechAUTHORS:20140326-113402727
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44529
Deposited By: Ruth Sustaita
Deposited On:26 Mar 2014 19:27
Last Modified:10 Nov 2021 16:53

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