Conformational dynamics of an intrinsically disordered receptor enable signal transduction

Signal transduction begins when cell-surface receptors interact with intracellular signaling proteins. While studies have outlined the molecular structure of receptor tyrosine kinase (RTK) signaling, the initial dynamic events connecting receptor activation to signal propagation have been elusive due to static structural snapshots or ensemble-averaged measurements from existing methods.

Employing high-speed atomic force microscopy (HS-AFM), researchers have now captured these initial molecular events in real-time at the single-molecule level. Using fibroblast growth factor receptor 1 (FGFR1) as a model, the study reveals that receptor autophosphorylation releases its intrinsically disordered juxtamembrane region, allowing significant conformational dynamics in the kinase domain.

This enables the receptor to effectively interact with the signaling adaptor FRS2, a crucial initiator of downstream RTK signaling. Conversely, a kinase-inactive mutation or the clinical FGFR inhibitor futibatinib limits receptor motion, stabilizes a compact form, and reduces adaptor engagement. Molecular dynamics simulations indicate that the liberation of inhibitory interactions between the juxtamembrane region and the kinase domain offers a structural rationale for the observed receptor dynamics.

These findings shed light on a previously unobserved physical mechanism driving RTK signaling initiation, affirming HS-AFM as a potent tool for visualizing receptor dynamics. This work not only lays a foundation for mechanistic studies of signal transduction but also guides the design and mechanistic assessment of compounds targeting receptor signaling.