8V55

Human mitochondrial DNA polymerase gamma bound to a replication fork in an open conformation

8V55 の概要

• エントリーDOI: 10.2210/pdb8v55/pdb
• EMDBエントリー: 42980
• 分子名称: DNA polymerase subunit gamma-1, DNA polymerase subunit gamma-2, mitochondrial, DNA primer chain, ... (4 entities in total)
• 機能のキーワード: dna binding protein, dna polymerase, mitochondrial dna replication, dna polymerase gamma, dna binding protein-dna complex, dna binding protein/dna
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 267491.57

構造登録者

Riccio, A.A.,Krahn, J.M.,Bouvette, J.,Borgnia, M.J.,Copeland, W.C. (登録日: 2023-11-30, 公開日: 2024-07-10, 最終更新日: 2024-07-31)

主引用文献

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

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: 38932681
DOI: 10.1093/nar/gkae539

実験手法

ELECTRON MICROSCOPY (4.2 Å)