6hc3

TFAM bound to Site-XTFAM bound to Site-X

Structural highlights

6hc3 is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	TFAM, TCF6, TCF6L2 (HUMAN)
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

Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM activates the mtDNA promoters LSP and HSP1 at the mtDNA control region where DNA regulatory elements cluster. Previous studies identified still uncharacterized, additional binding sites at the control region downstream from and slightly similar to LSP, namely sequences X and Y (Site-X and Site-Y) (Fisher et al., Cell 50, pp 247-258, 1987). Here, we explore TFAM binding at these two sites and compare them to LSP by multiple experimental and in silico methods. Our results show that TFAM binding is strongly modulated by the sequence-dependent properties of Site-X, Site-Y and LSP. The high binding versatility of Site-Y or the considerable stiffness of Site-X tune TFAM interactions. In addition, we show that increase in TFAM/DNA complex concentration induces multimerization, which at a very high concentration triggers disruption of preformed complexes. Therefore, our results suggest that mtDNA sequences induce non-uniform TFAM binding and, consequently, direct an uneven distribution of TFAM aggregation sites during the essential process of mtDNA compaction.

DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region.,Cuppari A, Fernandez-Millan P, Battistini F, Tarres-Sole A, Lyonnais S, Iruela G, Ruiz-Lopez E, Enciso Y, Rubio-Cosials A, Prohens R, Pons M, Alfonso C, Toth K, Rivas G, Orozco M, Sola M Nucleic Acids Res. 2019 May 22. pii: 5494731. doi: 10.1093/nar/gkz406. PMID:31114891^[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
↑ Cuppari A, Fernandez-Millan P, Battistini F, Tarres-Sole A, Lyonnais S, Iruela G, Ruiz-Lopez E, Enciso Y, Rubio-Cosials A, Prohens R, Pons M, Alfonso C, Toth K, Rivas G, Orozco M, Sola M. DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region. Nucleic Acids Res. 2019 May 22. pii: 5494731. doi: 10.1093/nar/gkz406. PMID:31114891 doi:http://dx.doi.org/10.1093/nar/gkz406

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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] Cuppari A, Fernandez-Millan P, Battistini F, Tarres-Sole A, Lyonnais S, Iruela G, Ruiz-Lopez E, Enciso Y, Rubio-Cosials A, Prohens R, Pons M, Alfonso C, Toth K, Rivas G, Orozco M, Sola M. DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region. Nucleic Acids Res. 2019 May 22. pii: 5494731. doi: 10.1093/nar/gkz406. PMID:31114891 doi:http://dx.doi.org/10.1093/nar/gkz406

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