Figure 7. Models of transcription activation by TFAM and mtDNA packaging.

(A), (B) Comparison of TFAM function on LSP versus HSP1. When bound on LSP (A), TFAM is oriented with the HMB-box B domain binding the distal half-site. As a result, the U-turn in DNA is necessary to position the C-terminal tail (small yellow region) towards the transcriptional machinery. The C-terminal tail is essential for transcriptional activation¹⁰ and physically interacts with TFB2M⁴⁵, but additional interactions with mtRNA polymerase are also possible. When bound to HSP1 (B), TFAM is oriented with the HMG-box B domain binding the proximal half-site. The C-terminal tail is positioned close to the transcriptional machinery, and DNA bending is dispensable for transcriptional activation. (C) Model of mtDNA compaction. Upon binding to mtDNA, each TFAM molecule imposes a local U-turn. When TFAM coats mtDNA, the formation of multiple U-turns results in mtDNA compaction. In addition, TFAM monomers can dimerize through the HMG-box A domain. This interaction forms DNA loops, which further compact mtDNA in the nucleoid.