Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants.
Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants.
复制标题
作者：
Blanden AR;Yu X;Blayney AJ;Demas C;Ha JH;Liu Y;Withers T;Carpizo DR;Loh SN
p53 DNA结合结构域（DBD）中的错义突变导致每年新发癌症病例的一半。在这里，我们提出了一个热力学模型，量化和链接的主要途径，突变p53。我们发现，DBD具有两个不寻常的属性之一，最高的锌亲和力的任何真核蛋白质和极端不稳定的情况下，锌，这是预测的p53的折叠/展开的尖端在细胞中，一个主要的决定因素是可用的锌浓度。我们分析了20种最常见的致瘤性p53突变，发现80%的突变损害了锌的亲和力、热力学稳定性或两者兼而有之。生物物理学、基于细胞的和鼠异种移植物实验表明，合成的锌金属伴侣不仅拯救降低锌亲和力的突变，而且拯救使DBD不稳定而不损害锌结合的突变。研究结果表明，锌金属伴侣在美国每年有能力治疗120，500名患者。
Missense mutations in the p53 DNA-binding domain (DBD) contribute to half of new cancer cases annually. Here we present a thermodynamic model that quantifies and links the major pathways by which mutations inactivate p53. We find that DBD possesses two unusual properties—one of the highest zinc affinities of any eukaryotic protein and extreme instability in the absence of zinc—which are predicted to poise p53 on the cusp of folding/unfolding in the cell, with a major determinant being available zinc concentration. We analyze the 20 most common tumorigenic p53 mutations and find that 80% impair zinc affinity, thermodynamic stability, or both. Biophysical, cell-based, and murine xenograft experiments demonstrate that a synthetic zinc metallochaperone rescues not only mutations that decrease zinc affinity, but also mutations that destabilize DBD without impairing zinc binding. The results suggest that zinc metallochaperones have the capability to treat 120,500 patients annually in the U.S.