8V5D
Human mitochondrial DNA polymerase catalytic subunit, PolG, in an APO conformation
Summary for 8V5D
| Entry DOI | 10.2210/pdb8v5d/pdb |
| EMDB information | 42982 |
| Descriptor | DNA polymerase subunit gamma-1 (1 entity in total) |
| Functional Keywords | dna binding protein, dna polymerase, mitochondrial dna replication, dna polymerase catalytic subunit, dna binding protein-dna complex, dna binding protein/dna |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 138723.44 |
| Authors | Riccio, A.A.,Brannon, A.J.,Krahn, J.M.,Bouvette, J.,Borgnia, J.M.,Copeland, W.C. (deposition date: 2023-11-30, release date: 2024-07-10, Last modification date: 2024-07-31) |
| Primary citation | Riccio, A.A.,Brannon, A.J.,Krahn, J.M.,Bouvette, J.,Williams, J.G.,Borgnia, M.J.,Copeland, W.C. Coordinated DNA polymerization by Pol gamma and the region of LonP1 regulated proteolysis. Nucleic Acids Res., 52:7863-7875, 2024 Cited by PubMed Abstract: The replicative mitochondrial DNA polymerase, Polγ, and its protein regulation are essential for the integrity of the mitochondrial genome. The intricacies of Polγ regulation and its interactions with regulatory proteins, which are essential for fine-tuning polymerase function, remain poorly understood. Misregulation of the Polγ heterotrimer, consisting of (i) PolG, the polymerase catalytic subunit and (ii) PolG2, the accessory subunit, ultimately results in mitochondrial diseases. Here, we used single particle cryo-electron microscopy to resolve the structure of PolG in its apoprotein state and we captured Polγ at three intermediates within the catalytic cycle: DNA bound, engaged, and an active polymerization state. Chemical crosslinking mass spectrometry, and site-directed mutagenesis uncovered the region of LonP1 engagement of PolG, which promoted proteolysis and regulation of PolG protein levels. PolG2 clinical variants, which disrupted a stable Polγ complex, led to enhanced LonP1-mediated PolG degradation. Overall, this insight into Polγ aids in an understanding of mitochondrial DNA replication and characterizes how machinery of the replication fork may be targeted for proteolytic degradation when improperly functioning. PubMed: 38932681DOI: 10.1093/nar/gkae539 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
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