T.C. Jenkins Department of Biophysics, Department of Biology, Johns Hopkins University, Baltimore, MD 21212, USA.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4134-9. doi: 10.1073/pnas.1120519109. Epub 2012 Mar 2.
Ligands for several transcription factors can act as agonists under some conditions and antagonists under others. The structural and molecular bases of such effects are unknown. Previously, we demonstrated how the folding of intrinsically disordered (ID) protein sequences, in particular, and population shifts, in general, could be used to mediate allosteric coupling between different functional domains, a model that has subsequently been validated in several systems. Here it is shown that population redistribution within allosteric systems can be used as a mechanism to tune protein ensembles such that a given ligand can act as both an agonist and an antagonist. Importantly, this mechanism can be robustly encoded in the ensemble, and does not require that the interactions between the ligand and the protein differ when it is acting either as an agonist or an antagonist. Instead, the effect is due to the relative probabilities of states prior to the addition of the ligand. The ensemble view of allostery that is illuminated by these studies suggests that rather than being seen as switches with fixed responses to allosteric activation, ensembles can evolve to be "functionally pluripotent," with the capacity to up or down regulate activity in response to a stimulus. This result not only helps to explain the prevalence of intrinsic disorder in transcription factors and other cell signaling proteins, it provides important insights about the energetic ground rules governing site-to-site communication in all allosteric systems.
配体与几个转录因子可以在某些条件下充当激动剂，而在其他条件下充当拮抗剂。这种影响的结构和分子基础尚不清楚。以前，我们展示了如何通过折叠无规则（ID）蛋白质序列，特别是通过群体转移，来介导不同功能域之间的变构偶联，这一模型随后在几个系统中得到了验证。在这里，我们表明，变构系统中的群体再分配可以作为一种机制来调节蛋白质集合，使得给定的配体既可以充当激动剂又可以充当拮抗剂。重要的是，这种机制可以在集合中得到稳健的编码，并且不需要配体与蛋白质相互作用在充当激动剂或拮抗剂时有所不同。相反，这种效果是由于配体加入之前状态的相对概率。这些研究揭示的变构的集合观点表明，与其将变构视为对变构激活具有固定响应的开关，不如将集合进化为“功能多能性”，具有根据刺激上调或下调活性的能力。这一结果不仅有助于解释转录因子和其他细胞信号转导蛋白中固有无序的普遍性，还为所有变构系统中站点间通讯的能量基本规则提供了重要的见解。
