Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.
Institute for Theoretical Physics, Heidelberg University, Philosophenweg 16, 69120, Heidelberg, Germany.
Nat Commun. 2020 May 8;11(1):2315. doi: 10.1038/s41467-020-15567-4.
As established nearly a century ago, mechanoradicals originate from homolytic bond scission in polymers. The existence, nature and biological relevance of mechanoradicals in proteins, instead, are unknown. We here show that mechanical stress on collagen produces radicals and subsequently reactive oxygen species, essential biological signaling molecules. Electron-paramagnetic resonance (EPR) spectroscopy of stretched rat tail tendon, atomistic molecular dynamics simulations and quantum-chemical calculations show that the radicals form by bond scission in the direct vicinity of crosslinks in collagen. Radicals migrate to adjacent clusters of aromatic residues and stabilize on oxidized tyrosyl radicals, giving rise to a distinct EPR spectrum consistent with a stable dihydroxyphenylalanine (DOPA) radical. The protein mechanoradicals, as a yet undiscovered source of oxidative stress, finally convert into hydrogen peroxide. Our study suggests collagen I to have evolved as a radical sponge against mechano-oxidative damage and proposes a mechanism for exercise-induced oxidative stress and redox-mediated pathophysiological processes.
近一个世纪前，机械自由基起源于聚合物中键的均裂。然而，蛋白质中的机械自由基的存在、性质和生物学相关性尚不清楚。我们在这里表明，胶原纤维受到机械应力会产生自由基和随后的活性氧物质，这是重要的生物信号分子。拉伸的大鼠尾腱的电子顺磁共振（EPR）光谱、原子分子动力学模拟和量子化学计算表明，自由基是通过胶原纤维中交联附近的键断裂形成的。自由基迁移到芳香族残基的相邻簇上，并在氧化的酪氨酸自由基上稳定下来，产生与稳定的二羟基苯丙氨酸（DOPA）自由基一致的独特 EPR 光谱。作为一种尚未被发现的氧化应激源，这种蛋白质机械自由基最终转化为过氧化氢。我们的研究表明，I 型胶原蛋白已经进化为一种对抗机械氧化损伤的自由基海绵，并提出了运动引起的氧化应激和氧化还原介导的病理生理过程的机制。
