Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Sci Adv. 2024 Nov 29;10(48):eadq8048. doi: 10.1126/sciadv.adq8048. Epub 2024 Nov 27.
The transduction of extracellular chemical signals into intracellular events relies on the communication between neighboring domains of membrane receptors. In the particular case of Cys-loop receptor channels, five short stretches of amino acids, one per subunit, link the extracellular and transmembrane domains in such a way that the ion permeability of the latter and the affinity for neurotransmitters of the former become tied to each other. Here, using direct functional approaches, we set out to understand the molecular bases of this crucial interdependence through the characterization of total loss-of-current mutations at the interface between domains. Our results indicate that domain-domain proximity plays a previously unnoticed critical role inasmuch as inserting a single residue in each linker rendered the two domains independent of each other. In marked contrast, loss-of-current mutations that leave the linkers' length unaltered did not compromise the interdomain coupling, but rather, seemed to cause agonist-bound closed receptors to desensitize without appreciably opening.
细胞外化学信号的转导依赖于膜受体相邻结构域之间的通讯。在 Cys 环受体通道的特殊情况下，五个短的氨基酸片段，每个亚基一个，将细胞外和跨膜结构域连接起来，使得后者的离子通透性和前者对神经递质的亲和力相互关联。在这里，我们通过对结构域界面的全电流缺失突变的特性分析，使用直接功能方法着手理解这种关键的相互依赖性的分子基础。我们的结果表明，结构域-结构域接近性起着以前未被注意到的关键作用，因为在每个连接子中插入单个残基，使得两个结构域相互独立。相比之下，不改变连接子长度的电流缺失突变不会破坏结构域间的偶联，但似乎会导致激动剂结合的关闭受体脱敏，而不会明显打开。
