Saha Pritam, Vashisht Vishavdeep, Singh Ojas, Sagar Amin, Bhati Gaurav Kumar, Garg Surbhi, Rakshit Sabyasachi
Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Punjab, India.
BicycleTx Limited, Cambridge, UK.
Nat Commun. 2025 Jan 25;16(1):1018. doi: 10.1038/s41467-025-55946-3.
Single-point mutations are pivotal in molecular zoology, shaping functions and influencing genetic diversity and evolution. Here we study three such genetic variants of a mechano-responsive protein, cadherin-23, that uphold the structural integrity of the protein, but showcase distinct genotypes and phenotypes. The variants exhibit subtle differences in transient intra-domain interactions, which in turn affect the anti-correlated motions among the constituent β-strands. In nature, the variants experience declining functions with aging at different rates. We expose these variants to constant and oscillatory forces using magnetic tweezer, and measure variations in stochastic folding dynamics. All variants exhibit multiple microstates under force. However, the protein variant with higher number of intra-domain interactions exhibits transitions among the heterogeneous microstates for larger extent of forces and persisted longer. Conversely, the protein variant with weaker inter-strand correlations exhibits greater unfolding cooperativity and faster intrinsic folding, although its folding-energy landscape is more susceptible to distortion under tension. Our study thus deciphers the molecular mechanisms underlying the variations in force-adaptations and proposes a mechanical relation between genotype and phenotype.
单点突变在分子动物学中至关重要，它塑造功能并影响遗传多样性和进化。在此，我们研究了一种机械响应蛋白——钙黏蛋白-23的三种此类遗传变体，这些变体维持了该蛋白的结构完整性，但展现出不同的基因型和表型。这些变体在瞬时域内相互作用上表现出细微差异，进而影响组成β链之间的反相关运动。在自然界中，这些变体随着衰老以不同速率出现功能衰退。我们使用磁镊将这些变体暴露于恒定和振荡力下，并测量随机折叠动力学的变化。所有变体在受力情况下均呈现多个微状态。然而，域内相互作用数量较多的蛋白变体在更大的力作用范围内，在异质微状态之间的转变程度更大且持续时间更长。相反，链间相关性较弱的蛋白变体展现出更大的去折叠协同性和更快的固有折叠速度，尽管其折叠能量景观在张力作用下更容易受到扭曲。因此，我们的研究揭示了力适应变化背后的分子机制，并提出了基因型与表型之间的力学关系。
