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人线粒体解旋酶 Twinkle 的 N 端结构域具有 DNA 结合活性,对聚合酶 γ 支持连续 DNA 合成至关重要。

The N-terminal domain of human mitochondrial helicase Twinkle has DNA-binding activity crucial for supporting processive DNA synthesis by polymerase γ.

机构信息

Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA; Graduate School of Biomedical Sciences, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.

Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.

出版信息

J Biol Chem. 2023 Jan;299(1):102797. doi: 10.1016/j.jbc.2022.102797. Epub 2022 Dec 14.

Abstract

Twinkle is the ring-shaped replicative helicase within the human mitochondria with high homology to bacteriophage T7 gp4 helicase-primase. Unlike many orthologs of Twinkle, the N-terminal domain (NTD) of human Twinkle has lost its primase activity through evolutionarily acquired mutations. The NTD has no demonstrated activity thus far; its role has remained unclear. Here, we biochemically characterize the isolated NTD and C-terminal domain (CTD) with linker to decipher their contributions to full-length Twinkle activities. This novel CTD construct hydrolyzes ATP, has weak DNA unwinding activity, and assists DNA polymerase γ (Polγ)-catalyzed strand-displacement synthesis on short replication forks. However, CTD fails to promote multikilobase length product formation by Polγ in rolling-circle DNA synthesis. Thus, CTD retains all the motor functions but struggles to implement them for processive translocation. We show that NTD has DNA-binding activity, and its presence stabilizes Twinkle oligomerization. CTD oligomerizes on its own, but the loss of NTD results in heterogeneously sized oligomeric species. The CTD also exhibits weaker and salt-sensitive DNA binding compared with full-length Twinkle. Based on these results, we propose that NTD directly contributes to DNA binding and holds the DNA in place behind the central channel of the CTD like a "doorstop," preventing helicase slippages and sustaining processive unwinding. Consistent with this model, mitochondrial single-stranded DNA-binding protein (mtSSB) compensate for the NTD loss and partially restore kilobase length DNA synthesis by CTD and Polγ. The implications of our studies are foundational for understanding the mechanisms of disease-causing Twinkle mutants that lie in the NTD.

摘要

Twinkle 是人类线粒体中的环状复制解旋酶,与噬菌体 T7 gp4 解旋酶-引物酶具有高度同源性。与许多 Twinkle 的同源物不同,人类 Twinkle 的 N 端结构域(NTD)通过进化获得的突变失去了其引物酶活性。迄今为止,NTD 没有表现出任何活性;其作用仍然不清楚。在这里,我们通过生化手段对分离的 NTD 和 C 端结构域(CTD)与连接体进行了表征,以阐明它们对全长 Twinkle 活性的贡献。这种新型 CTD 构建体水解 ATP,具有较弱的 DNA 解旋活性,并辅助 DNA 聚合酶 γ(Polγ)在短复制叉上进行链置换合成。然而,CTD 无法促进 Polγ 在滚环 DNA 合成中形成多千碱基长度的产物。因此,CTD 保留了所有的运动功能,但难以实现其进行性易位。我们表明 NTD 具有 DNA 结合活性,其存在稳定了 Twinkle 的寡聚化。CTD 可以自身寡聚化,但 NTD 的缺失会导致寡聚化物种大小不均一。与全长 Twinkle 相比,CTD 也表现出较弱和对盐敏感的 DNA 结合能力。基于这些结果,我们提出 NTD 直接有助于 DNA 结合,并像“门挡”一样将 DNA 固定在 CTD 的中央通道后面,防止解旋酶滑动并维持进行性解旋。与该模型一致,线粒体单链 DNA 结合蛋白(mtSSB)弥补了 NTD 的缺失,并通过 CTD 和 Polγ 部分恢复了千碱基长度的 DNA 合成。我们的研究结果对于理解位于 NTD 的致病 Twinkle 突变体的机制具有基础性意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fde7/9860392/24cccb83b692/gr1.jpg

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