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高精确度 FRET 研究揭示了微秒到分钟之间核小体的可逆转变。

High precision FRET studies reveal reversible transitions in nucleosomes between microseconds and minutes.

机构信息

DKFZ, Div. Biophysics of Macromolecules, 69120, Heidelberg, Germany.

Heinrich-Heine-Universität, Lehrstuhl für Molekulare Physikalische Chemie, Düsseldorf, 40225, Germany.

出版信息

Nat Commun. 2018 Nov 6;9(1):4628. doi: 10.1038/s41467-018-06758-1.

DOI:10.1038/s41467-018-06758-1
PMID:30401903
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6219519/
Abstract

Nucleosomes play a dual role in compacting the genome and regulating the access to DNA. To unravel the underlying mechanism, we study fluorescently labeled mononucleosomes by multi-parameter FRET measurements and characterize their structural and dynamic heterogeneity upon NaCl-induced destabilization. Species-selective fluorescence lifetime analysis and dynamic photon distribution analysis reveal intermediates during nucleosome opening and lead to a coherent structural and kinetic model. In dynamic octasomes and hexasomes the interface between the H2A-H2B dimers and the (H3-H4) tetramer opens asymmetrically by an angle of ≈20° on a 50 and 15 µs time scale, respectively. This is followed by a slower stepwise release of the dimers coupled with DNA unwrapping. A mutation (H2A-R81A) at the interface between H2A and H3 facilitates initial opening, confirming the central role of the dimer:tetramer interface for nucleosome stability. Partially opened states such as those described here might serve as convenient nucleation sites for DNA-recognizing proteins.

摘要

核小体在压缩基因组和调节 DNA 可及性方面发挥着双重作用。为了揭示其潜在机制，我们通过多参数Förster 共振能量转移（FRET）测量研究了荧光标记的单核小体，并在 NaCl 诱导的去稳定化过程中对其结构和动态异质性进行了表征。种属选择性荧光寿命分析和动态光子分布分析揭示了核小体打开过程中的中间状态，并提出了一个连贯的结构和动力学模型。在动态八聚体和六聚体中，H2A-H2B 二聚体和(H3-H4)四聚体之间的界面分别以约 20°的角度不对称打开，时间尺度分别为 50 和 15 μs。随后，二聚体与 DNA 解缠绕的逐步释放速度较慢。在 H2A 和 H3 之间的界面处的突变（H2A-R81A）促进了初始打开，证实了二聚体：四聚体界面在核小体稳定性方面的核心作用。像这里描述的部分打开状态可能作为 DNA 识别蛋白的方便成核位点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/2c4b40059d18/41467_2018_6758_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/71b8d9434ed0/41467_2018_6758_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/a69420b281e4/41467_2018_6758_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/b7068a49677c/41467_2018_6758_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/8beb01f02da8/41467_2018_6758_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/0eeb4b7df80a/41467_2018_6758_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/45ac5a55ee9f/41467_2018_6758_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/b4a33628913b/41467_2018_6758_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/2c4b40059d18/41467_2018_6758_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/71b8d9434ed0/41467_2018_6758_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/a69420b281e4/41467_2018_6758_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/b7068a49677c/41467_2018_6758_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/8beb01f02da8/41467_2018_6758_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/0eeb4b7df80a/41467_2018_6758_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/45ac5a55ee9f/41467_2018_6758_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/b4a33628913b/41467_2018_6758_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9565/6219519/2c4b40059d18/41467_2018_6758_Fig8_HTML.jpg

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