School of Applied and Engineering Physics, Cornell University, Ithaca, NY, 14853, USA.
Center for Biophysics and Quantitative Biology, University of Illinois Urbana Champaign, Urbana, IL, 61801, USA.
Nat Commun. 2024 Sep 10;15(1):7901. doi: 10.1038/s41467-024-51972-9.
Poly(ADP-ribose) (PAR), a non-canonical nucleic acid, is essential for DNA/RNA metabolism and protein condensation, and its dysregulation is linked to cancer and neurodegeneration. However, key structural insights into PAR's functions remain largely uncharacterized, hindered by the challenges in synthesizing and characterizing PAR, which are attributed to its length heterogeneity. A central issue is how PAR, comprised solely of ADP-ribose units, attains specificity in its binding and condensing proteins based on chain length. Here, we integrate molecular dynamics simulations with small-angle X-ray scattering to analyze PAR structures. We identify diverse structural ensembles of PAR that fall into distinct subclasses and reveal distinct compaction of two different lengths of PAR upon the addition of small amounts of Mg ions. Unlike PAR, PAR forms ADP-ribose bundles via local intramolecular coil-to-globule transitions. Understanding these length-dependent structural changes could be central to deciphering the specific biological functions of PAR.
多聚（ADP-核糖）（PAR）是一种非典型的核酸，对 DNA/RNA 代谢和蛋白质凝聚至关重要，其失调与癌症和神经退行性疾病有关。然而，PAR 功能的关键结构见解在很大程度上仍未得到描述，这是由于 PAR 的合成和表征具有挑战性，这归因于其长度异质性。一个核心问题是，仅由 ADP-核糖单元组成的 PAR 如何根据链长获得与其结合和浓缩蛋白质的特异性。在这里，我们将分子动力学模拟与小角度 X 射线散射相结合，以分析 PAR 结构。我们确定了 PAR 的不同结构集合，这些集合分为不同的子类，并揭示了在添加少量 Mg 离子后，两种不同长度的 PAR 的不同程度的压缩。与 PAR 不同，PAR 通过局部分子内螺旋到球的转变形成 ADP-核糖束。理解这些依赖长度的结构变化可能是破译 PAR 特定生物学功能的关键。
Zotero 插件
