Kavran Jennifer M, McCabe Jacqueline M, Byrne Patrick O, Connacher Mary Katherine, Wang Zhihong, Ramek Alexander, Sarabipour Sarvenaz, Shan Yibing, Shaw David E, Hristova Kalina, Cole Philip A, Leahy Daniel J
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.
Elife. 2014 Sep 25;3:e03772. doi: 10.7554/eLife.03772.
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.
I型胰岛素样生长因子受体（IGF1R）参与正常细胞和肿瘤细胞的生长与存活。配体依赖性构象变化被认为可调节IGF1R活性，但这种变化的本质尚不清楚。我们指出，在结合胰岛素的相关胰岛素受体（IR）晶体结构中存在一个未被充分认识的二聚体，这使得我们能够直接将其与未结合配体的IR进行比较，并提出了一种配体调节IR/IGF1R活性的机制。我们在一系列生化和生物物理实验中对该机制进行了测试，发现IGF1R胞外域维持一种自抑制状态，其中跨膜区（TMs）相互分离。配体结合解除了这种限制，使得TMs能够结合，并释放细胞内区域自身磷酸化的内在倾向。对全长和含激酶片段的酶学研究表明，磷酸化的IGF1R完全具有活性，且不依赖于配体和细胞外-TM区域。因此，配体结合触发的关键步骤是自身磷酸化。
