The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA

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Abstract
The mitochondrial transcription factor Tfam has a role in organizing the mitochondrial genome, in addition to its transcriptional function. Structural studies of human Tfam in complex with a mitochondrial DNA promoter show that Tfam imposes a U-turn on the DNA similarly to the unrelated HU family of proteins, which play analogous architectural roles in organizing bacterial nucleoids. Tfam (transcription factor A, mitochondrial), a DNA-binding protein with tandem high-mobility group (HMG)-box domains, has a central role in the expression, maintenance and organization of the mitochondrial genome. It activates transcription from mitochondrial promoters and organizes the mitochondrial genome into nucleoids. Using X-ray crystallography, we show that human Tfam forces promoter DNA to undergo a U-turn, reversing the direction of the DNA helix. Each HMG-box domain wedges into the DNA minor groove to generate two kinks on one face of the DNA. On the opposite face, a positively charged α-helix serves as a platform to facilitate DNA bending. The structural principles underlying DNA bending converge with those of the unrelated HU family proteins, which have analogous architectural roles in organizing bacterial nucleoids. The functional importance of this extreme DNA bending is promoter specific and seems to be related to the orientation of Tfam on the promoters.