Ross G M, Shamovsky I L, Lawrance G, Solc M, Dostaler S M, Weaver D F, Riopelle R J
Department of Medicine, Kingston General Hospital, Ontario, Canada.
Eur J Neurosci. 1998 Mar;10(3):890-8. doi: 10.1046/j.1460-9568.1998.00094.x.
Equilibrium binding of 125I-nerve growth factor (125I-NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotrophin receptor (p75NTR), cells coexpressing both receptors where p75NTR is occupied, and cells expressing only p75NTR, revealed reciprocal modulation of receptor affinity states. Analysis of receptor affinity states in PC12 cells, PC12 cells in the presence of brain-derived neurotrophic factor (BDNF), and PC12nnr5 cells suggested that liganded and unliganded p75NTR induce a higher affinity state within TrkA, while TrkA induces a lower affinity state within p75NTR. These data are consistent with receptor allosterism, and prompted a search for TrkA/p75NTR complexes in the absence of NGF. Chemical crosslinking studies revealed high molecular weight receptor complexes that specifically bound 125I-NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75NTR alters conformation and/or dissociates in the presence of NGF, as indicated by the ability of low concentrations of NGF to prevent heteroreceptor crosslinking. These data suggest a new model of receptor interaction, whereby structural changes within a heteroreceptor complex are induced by ligand binding.
125I-神经生长因子（125I-NGF）与共表达酪氨酸激酶受体A（TrkA）和常见神经营养因子受体（p75NTR）的细胞、p75NTR被占据时共表达这两种受体的细胞以及仅表达p75NTR的细胞的平衡结合，揭示了受体亲和状态的相互调节。对PC12细胞、存在脑源性神经营养因子（BDNF）时的PC12细胞以及PC12nnr5细胞中受体亲和状态的分析表明，结合配体和未结合配体的p75NTR在TrkA内诱导更高的亲和状态，而TrkA在p75NTR内诱导更低的亲和状态。这些数据与受体别构现象一致，并促使人们在没有NGF的情况下寻找TrkA/p75NTR复合物。化学交联研究揭示了特异性结合125I-NGF且能被针对两种受体的抗体免疫沉淀的高分子量受体复合物。低浓度NGF能够阻止异源受体交联，这表明在NGF存在的情况下，TrkA和p75NTR的异源受体复合物会改变构象和/或解离。这些数据提示了一种新的受体相互作用模型，即配体结合会诱导异源受体复合物内的结构变化。
