Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation.
Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation.
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DOI：
10.1038/ncomms4077
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发表时间：
2014
影响因子：
16.6
通讯作者：
Chan, David C
中科院分区：
文献类型：
--
作者：
Ngo, Huu B;Lovely, Geoffrey A;Phillips, Rob;Chan, David C
TFAM 是一种 DNA 结合蛋白，可激活线粒体 DNA 的两个主要启动子——轻链启动子 (LSP) 和重链启动子 1 (HSP1) 处的转录。同样重要的是，它包裹并包装线粒体基因组。 TFAM 已被证明可以对 LSP DNA 进行 U 型转变，但这种扭曲是否与其他位点相关尚不清楚。在这里，我们展示了与 HSP1 和非特异性 DNA 结合的 TFAM 的晶体结构。在这两种情况下，TFAM 都会类似地将 DNA 扭曲成 U 型转弯。然而，TFAM 与 HSP1 的结合方向与 LSP 相反，这解释了为什么 LSP 的转录需要 DNA 弯曲，而 HSP1 的转录则不需要。此外，晶体结构揭示了 DNA 结合 TFAM 的二聚化。这种二聚化对于 DNA 弯曲和转录激活来说是可有可无的，但对于 DNA 压缩却很重要。我们提出 TFAM 二聚化通过促进 DNA 成环来增强线粒体 DNA 压缩。
TFAM is a DNA binding protein that activates transcription at the two major promoters of mitochondrial DNA — the light strand promoter (LSP) and heavy strand promoter 1 (HSP1). Equally important, it coats and packages the mitochondrial genome. TFAM has been shown to impose a U-turn on LSP DNA, but whether this distortion is relevant at other sites is unknown. Here, we present crystal structures of TFAM bound to HSP1 and to nonspecific DNA. In both, TFAM similarly distorts the DNA into a U-turn. Yet, TFAM binds to HSP1 in the opposite orientation from LSP explaining why transcription from LSP requires DNA bending, whereas transcription at HSP1 does not. Moreover, the crystal structures reveal dimerization of DNA-bound TFAM. This dimerization is dispensable for DNA bending and transcriptional activation, but important in DNA compaction. We propose that TFAM dimerization enhances mitochondrial DNA compaction by promoting looping of the DNA.