Acetylation and phosphorylation of human TFAM regulate TFAM-DNA interactions via contrasting mechanisms
| Autor: | Kees-Karel H. Taris, Graeme A. King, Wouter H. Roos, Kamalendra Singh, Maryam Hashemi Shabestari, Ashutosh K. Pandey, J. Thilagavathi, Dmitry Temiakov, Carolyn K. Suzuki, Sundararajan Venkatesh, Gijs J.L. Wuite, Rama K. Koppisetti |
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| Přispěvatelé: | Molecular Biophysics, Physics of Living Systems, LaserLaB - Molecular Biophysics |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mitochondrial DNA Transcription Genetic Biology DNA-binding protein DNA Mitochondrial Serine Mitochondrial Proteins 03 medical and health sciences chemistry.chemical_compound INITIATION 0302 clinical medicine Transcription (biology) MTDNA Genetics Humans Phosphorylation Promoter Regions Genetic Transcription factor FACTOR-A NUCLEOIDS Nucleic Acid Enzymes MITOCHONDRIAL TRANSCRIPTION FACTOR NONCOOPERATIVE BINDING Acetylation MICROSCOPY TFAM Cell biology PROTEIN INTERACTIONS DNA-Binding Proteins Kinetics 030104 developmental biology chemistry Phosphoserine CELLS REPLICATION 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Nucleic Acids Research, 46(7), 3633-3642. Oxford University Press Shabestari, M H, King, G A, Taris, K-K H, Pandey, A K, Venkatesh, S, Thilagavathi, J, Singh, K, Koppisetti, R K, Temiakov, D, Roos, W H, Suzuki, C K & Wuite, G J L 2018, ' Acetylation and phosphorylation of human TFAM regulate TFAM-DNA interactions via contrasting mechanisms ', Nucleic Acids Research, vol. 46, no. 7, pp. 3633-3642 . https://doi.org/10.1093/nar/gky204 Nucleic Acids Research |
| ISSN: | 0305-1048 |
| Popis: | Mitochondrial transcription factor A (TFAM) is essential for the maintenance, expression and transmission of mitochondrial DNA (mtDNA). However, mechanisms for the post-translational regulation of TFAM are poorly understood. Here, we show that TFAM is lysine acetylated within its high-mobility-group box 1, a domain that can also be serine phosphorylated. Using bulk and single-molecule methods, we demonstrate that site-specific phosphoserine and acetyl-lysine mimics of human TFAM regulate its interaction with non-specific DNA through distinct kinetic pathways. We show that higher protein concentrations of both TFAM mimics are required to compact DNA to a similar extent as the wild-type. Compaction is thought to be crucial for regulating mtDNA segregation and expression. Moreover, we reveal that the reduced DNA binding affinity of the acetyl-lysine mimic arises from a lower on-rate, whereas the phosphoserine mimic displays both a decreased on-rate and an increased off-rate. Strikingly, the increased off-rate of the phosphoserine mimic is coupled to a significantly faster diffusion of TFAM on DNA. These findings indicate that acetylation and phosphorylation of TFAM can fine-tune TFAM–DNA binding affinity, to permit the discrete regulation of mtDNA dynamics. Furthermore, our results suggest that phosphorylation could additionally regulate transcription by altering the ability of TFAM to locate promoter sites. |
| Databáze: | OpenAIRE |
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