Lee Young-Sam, Kennedy W Dexter, Yin Y Whitney
Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
Cell. 2009 Oct 16;139(2):312-24. doi: 10.1016/j.cell.2009.07.050.
Human mitochondrial DNA polymerase (Pol gamma) is the sole replicase in mitochondria. Pol gamma is vulnerable to nonselective antiretroviral drugs and is increasingly associated with mutations found in patients with mitochondriopathies. We determined crystal structures of the human heterotrimeric Pol gamma holoenzyme and, separately, a variant of its processivity factor, Pol gammaB. The holoenzyme structure reveals an unexpected assembly of the mitochondrial DNA replicase where the catalytic subunit Pol gammaA interacts with its processivity factor primarily via a domain that is absent in all other DNA polymerases. This domain provides a structural module for supporting both the intrinsic processivity of the catalytic subunit alone and the enhanced processivity of holoenzyme. The Pol gamma structure also provides a context for interpreting the phenotypes of disease-related mutations in the polymerase and establishes a foundation for understanding the molecular basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase.
人类线粒体DNA聚合酶（Polγ）是线粒体中的唯一复制酶。Polγ易受非选择性抗逆转录病毒药物的影响，并且越来越多地与线粒体病患者中发现的突变相关。我们确定了人类异源三聚体Polγ全酶的晶体结构，以及其持续性因子PolγB的一个变体的晶体结构。全酶结构揭示了线粒体DNA复制酶的一种意外组装方式，其中催化亚基PolγA主要通过一个在所有其他DNA聚合酶中都不存在的结构域与其持续性因子相互作用。该结构域提供了一个结构模块，既支持单独催化亚基的内在持续性，也支持全酶增强的持续性。Polγ结构还为解释聚合酶中与疾病相关突变的表型提供了背景，并为理解靶向HIV逆转录酶的抗逆转录病毒药物毒性的分子基础奠定了基础。
