IRIBHM, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium.
Nat Commun. 2012;3:1007. doi: 10.1038/ncomms1991.
Glycoprotein hormone receptors show strong negative cooperativity. As a consequence, at physiological hormone concentrations, a single agonist binds to a receptor dimer. Here we present evidence that constitutively active receptors lose cooperative allosteric regulation in direct relation with their basal activity. The most constitutive mutants lost nearly all cooperativity and showed an increase of initial tracer binding, reflecting the ability of each protomer to bind with equal affinity. Allosteric interaction between the protomers takes place at the transmembrane domain. The allosteric message resulting from hormone binding to the ectodomain of one protomer travels 'downward' to its transmembrane domain, before affecting the transmembrane domain of the other protomer. This results in transmission of an 'upward' message lowering the binding affinity of the ectodomain of the second protomer. Our results demonstrate a direct relation between the conformational changes associated with activation of the transmembrane domain and the allosteric behaviour of glycoprotein hormone receptors dimers.
糖蛋白激素受体表现出强烈的负协同性。因此，在生理激素浓度下，单个激动剂结合到受体二聚体上。在这里，我们提供的证据表明，组成型激活的受体与其基础活性直接相关而失去协同变构调节。最组成型的突变体几乎失去了所有的协同性，并表现出初始示踪剂结合的增加，反映了每个单体以相等的亲和力结合的能力。单体之间的变构相互作用发生在跨膜域。从激素结合到一个单体的细胞外结构域的变构信息“向下”传递到其跨膜域，然后影响另一个单体的跨膜域。这导致传递“向上”的信息，降低第二个单体的细胞外结构域的结合亲和力。我们的结果表明，与跨膜域激活相关的构象变化与糖蛋白激素受体二聚体的变构行为之间存在直接关系。
