4nod

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

Structural highlights

4nod is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.897Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TFAM_HUMAN Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation. Required for accurate and efficient promoter recognition by the mitochondrial RNA polymerase. Promotes transcription initiation from the HSP1 and the light strand promoter by binding immediately upstream of transcriptional start sites. Is able to unwind DNA. Bends the mitochondrial light strand promoter DNA into a U-turn shape via its HMG boxes. Required for maintenance of normal levels of mitochondrial DNA. May play a role in organizing and compacting mitochondrial DNA.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

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.

Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation.,Ngo HB, Lovely GA, Phillips R, Chan DC Nat Commun. 2014 Jan 17;5:3077. doi: 10.1038/ncomms4077. PMID:24435062^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Fisher RP, Lisowsky T, Parisi MA, Clayton DA. DNA wrapping and bending by a mitochondrial high mobility group-like transcriptional activator protein. J Biol Chem. 1992 Feb 15;267(5):3358-67. PMID:1737790
↑ Litonin D, Sologub M, Shi Y, Savkina M, Anikin M, Falkenberg M, Gustafsson CM, Temiakov D. Human mitochondrial transcription revisited: only TFAM and TFB2M are required for transcription of the mitochondrial genes in vitro. J Biol Chem. 2010 Jun 11;285(24):18129-33. doi: 10.1074/jbc.C110.128918. Epub, 2010 Apr 21. PMID:20410300 doi:http://dx.doi.org/10.1074/jbc.C110.128918
↑ Gangelhoff TA, Mungalachetty PS, Nix JC, Churchill ME. Structural analysis and DNA binding of the HMG domains of the human mitochondrial transcription factor A. Nucleic Acids Res. 2009 Jun;37(10):3153-64. Epub 2009 Mar 20. PMID:19304746 doi:10.1093/nar/gkp157
↑ Rubio-Cosials A, Sidow JF, Jimenez-Menendez N, Fernandez-Millan P, Montoya J, Jacobs HT, Coll M, Bernado P, Sola M. Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. Nat Struct Mol Biol. 2011 Oct 30;18(11):1281-9. doi: 10.1038/nsmb.2160. PMID:22037172 doi:10.1038/nsmb.2160
↑ Ngo HB, Kaiser JT, Chan DC. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol. 2011 Oct 30;18(11):1290-6. doi: 10.1038/nsmb.2159. PMID:22037171 doi:10.1038/nsmb.2159
↑ Ngo HB, Lovely GA, Phillips R, Chan DC. Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat Commun. 2014 Jan 17;5:3077. doi: 10.1038/ncomms4077. PMID:24435062 doi:http://dx.doi.org/10.1038/ncomms4077

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OCA

[1] Fisher RP, Lisowsky T, Parisi MA, Clayton DA. DNA wrapping and bending by a mitochondrial high mobility group-like transcriptional activator protein. J Biol Chem. 1992 Feb 15;267(5):3358-67. PMID:1737790

[2] Litonin D, Sologub M, Shi Y, Savkina M, Anikin M, Falkenberg M, Gustafsson CM, Temiakov D. Human mitochondrial transcription revisited: only TFAM and TFB2M are required for transcription of the mitochondrial genes in vitro. J Biol Chem. 2010 Jun 11;285(24):18129-33. doi: 10.1074/jbc.C110.128918. Epub, 2010 Apr 21. PMID:20410300 doi:http://dx.doi.org/10.1074/jbc.C110.128918

[3] Gangelhoff TA, Mungalachetty PS, Nix JC, Churchill ME. Structural analysis and DNA binding of the HMG domains of the human mitochondrial transcription factor A. Nucleic Acids Res. 2009 Jun;37(10):3153-64. Epub 2009 Mar 20. PMID:19304746 doi:10.1093/nar/gkp157

[4] Rubio-Cosials A, Sidow JF, Jimenez-Menendez N, Fernandez-Millan P, Montoya J, Jacobs HT, Coll M, Bernado P, Sola M. Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter. Nat Struct Mol Biol. 2011 Oct 30;18(11):1281-9. doi: 10.1038/nsmb.2160. PMID:22037172 doi:10.1038/nsmb.2160

[5] Ngo HB, Kaiser JT, Chan DC. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol. 2011 Oct 30;18(11):1290-6. doi: 10.1038/nsmb.2159. PMID:22037171 doi:10.1038/nsmb.2159

[6] Ngo HB, Lovely GA, Phillips R, Chan DC. Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat Commun. 2014 Jan 17;5:3077. doi: 10.1038/ncomms4077. PMID:24435062 doi:http://dx.doi.org/10.1038/ncomms4077

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