Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
Protein Sci. 2022 May;31(5):e4298. doi: 10.1002/pro.4298.
Heterooligomers that undergo ligand-promoted conformational changes are ubiquitous in nature and involved in many essential processes. Conformational switching often leads to positive cooperativity in ligand binding that is reflected in a Hill coefficient with a value greater than one. The subunits comprising heterooligomers can differ, however, in their affinity for the ligand. Such so-called site heterogeneity results in apparent negative cooperativity that is reflected by a Hill coefficient with a value less than one. Consequently, positive cooperativity due to the ligand-promoted allosteric switch can be masked, in cases of such heterooligomers, by apparent negative cooperativity owing to site heterogeneity. Here, we derived expressions for the Hill coefficient, in the case of a heterodimer, in which the contributions from the ligand-promoted allosteric switch and site heterogeneity are separated. Using these equations and simulations for higher order oligomers, we show under which conditions site heterogeneity can significantly mask the extent of observed positive cooperativity.
经历配体促进的构象变化的杂寡聚体在自然界中无处不在，参与许多重要的过程。构象转换通常导致配体结合的正协同性，这反映在大于 1 的 Hill 系数上。然而，组成杂寡聚体的亚基在对配体的亲和力上可能不同。这种所谓的位点异质性导致表观负协同性，这反映在小于 1 的 Hill 系数上。因此，在这种杂寡聚体的情况下，由于配体促进的变构开关引起的正协同性可能由于位点异质性而被表观负协同性掩盖。在这里，我们推导出了杂二聚体情况下的 Hill 系数表达式，其中分离了配体促进的变构开关和位点异质性的贡献。使用这些方程和更高阶寡聚体的模拟，我们展示了在哪些条件下，位点异质性可以显著掩盖观察到的正协同性的程度。
