Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms (TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligands NT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways, whereas PTP-sigma activates biased signals. Our data support an “in-to-out” model controlling receptor ectodomain conformation, a strategy that enables heterogeneity in receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.

受体胞外域的事件影响细胞内结构域构象，激活信号转导（从外到内的构象效应）。我们研究了细胞内结构域可能影响胞外结构域的相反方向（从内到外）。天然存在的 TrkC 受体亚型（TrkC-FL 和 TrkC.T1）的一级序列仅在细胞内结构域有所不同。然而，由于它们与蛋白质二硫键异构酶的不同关联，这些亚型在胞外域具有不同的二硫键和构象。利用构象开发人工配体、单克隆抗体和小分子，具有异构体特异性结合和偏向激活。一致的是，生理配体 NT-3 和 PTP-sigma 结合两种异构体，但 NT-3 激活所有信号通路，而 PTP-sigma 激活偏向信号。我们的数据支持控制受体胞外域构象的“从内到外”模型，该策略可以实现受体、配体和生物活性的异质性。这些概念可以扩展到许多具有已知亚型的野生型或致癌受体。