Figure 2. TFAM differentially regulates mtDNA promoters and packages mtDNA.

TFAM is a multi-functional protein. (A) TFAM activation of transcription at the LSP is shown. TFAM, via its C-terminal tail that interacts with TFB2M (green) and unique DNA-bending capacity, promotes high levels of specific initiation by POLRMT (blue) and TFB2M. (B) TFAM can also inhibit transcription at HSP2 in vitro at concentrations that activate LSP and HSP1. It is postulated that this is due to a unique binding mode at this site that competitively inhibits promoter binding by POLRMT and TFB2M. C) In addition to its role in transcription, TFAM also packages mtDNA to facilitate nucleoid formation. This is accomplished by its ability to bind many sites on mtDNA in a more or less nonspecific manner and bend the DNA, albeit to a lesser degree than promoter DNA. TFAM is phosphorylated at sites within the HMG-box domains (denoted as round circles with a “P”), which reduces DNA binding and promotes its degradation by Lon protease. This may allow dynamic remodeling of nucleoids to achieve specific outcomes (e.g. to relieve inhibition of HSP2 transcription). TFAM: transcription factor A mitochondrial, TFB2M: transcription factor B2 mitochondrial, POLRMT: mitochondrial RNA polymerase, LSP: light-strand promoter, HSP: heavy-strand promoter, mtDNA: mitochondrial DNA, HMG box: high-mobility-group box.