Acosta Karen, Brue Christopher R, Holubovska Polina, Kim Hee Jong, Mayne Leland, Murakami Kenji, Rhoades Elizabeth
Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Structure. 2025 Mar 6;33(3):465-474.e8. doi: 10.1016/j.str.2024.12.017. Epub 2025 Jan 17.
Tau plays an important role in modulating axonal microtubules in neurons, while intracellular tau aggregates are found in many neurodegenerative disorders. Tubulin binding sites are found in tau's proline-rich region (PRR), microtubule binding repeats (MTBRs), and pseudo-repeat (R'). Tau phosphorylation sites, which cluster with high frequency within the PRR, regulate tubulin interactions and correlates with disease. Here, we use fluorescence correlation spectroscopy and structural mass spectrometry techniques to characterize the impact of phosphomimic mutations in the PRR on tau function. We find that phosphomimics cumulatively diminish tubulin dimer binding and slow microtubule polymerization. Additionally, we map two ∼15 residue regions of the PRR as primary tubulin dimer binding sites and propose a model in which PRR enhances lateral interactions between tubulin dimers, complementing the longitudinal interactions observed for MTBR. Our study provides insight into the previously overlooked relevance of tau's PRR in functional interactions with tubulin dimers.
tau蛋白在调节神经元轴突微管中发挥重要作用，而细胞内tau蛋白聚集体存在于许多神经退行性疾病中。微管蛋白结合位点存在于tau蛋白的富含脯氨酸区域（PRR）、微管结合重复序列（MTBRs）和假重复序列（R'）中。tau蛋白磷酸化位点在PRR内高频聚集，调节微管蛋白相互作用并与疾病相关。在此，我们使用荧光相关光谱和结构质谱技术来表征PRR中磷酸模拟突变对tau蛋白功能的影响。我们发现磷酸模拟物会累积减少微管蛋白二聚体结合并减缓微管聚合。此外，我们将PRR的两个约15个残基的区域定位为主要的微管蛋白二聚体结合位点，并提出了一个模型，其中PRR增强微管蛋白二聚体之间的横向相互作用，补充了MTBR观察到的纵向相互作用。我们的研究深入了解了tau蛋白PRR在与微管蛋白二聚体功能相互作用中先前被忽视的相关性。
