Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
J Mol Biol. 2018 Aug 3;430(16):2468-2477. doi: 10.1016/j.jmb.2018.04.004. Epub 2018 Apr 11.
The BCL-2 family of proteins plays a central role in regulating cell survival and apoptosis. Disordered BH3-only proteins bind promiscuously to a number of different BCL-2 proteins, with binding affinities that vary by orders of magnitude. Here we investigate the basis for these differences in affinity. We show that eight different disordered BH3 proteins all bind to their BCL-2 partner (MCL-1) very rapidly, and that the differences in sequences result in different dissociation rates. Similarly, mutation of the binding surface of MCL-1 generally affects association kinetics in the same way for all BH3 peptides but has significantly different effects on the dissociation rates. Importantly, we infer that the evolution of homologous, competing interacting partners has resulted in complexes with significantly different lifetimes.
BCL-2 家族蛋白在调节细胞存活和凋亡方面起着核心作用。紊乱的 BH3 仅蛋白随机结合到许多不同的 BCL-2 蛋白上，结合亲和力相差几个数量级。在这里，我们研究了这些亲和力差异的基础。我们表明，八种不同的紊乱 BH3 蛋白都能非常迅速地与它们的 BCL-2 伙伴（MCL-1）结合，并且序列的差异导致了不同的解离率。同样，MCL-1 结合表面的突变通常以相同的方式影响所有 BH3 肽的结合动力学，但对解离率的影响却大不相同。重要的是，我们推断出同源竞争相互作用伙伴的进化导致了具有显著不同寿命的复合物。
