Glycosylation-Modulated Conformational Diversity in Neurotrophin Receptors

Abstract

Glycosylation is a widespread modification of cell-surface receptors, yet its structural impact is often overlooked due to the difficulty of experimentally characterizing glycans. Glycosylation of neurotrophin receptors has been reported to affect their localization and function. To investigate the effects of glycosylation of the extracellular domains (ECDs) of p75, TrkA, and TrkB neurotrophin receptors, we modeled their ECDs in glycosylated and non-glycosylated states and carried out molecular dynamics simulations of monomeric and dimeric forms of the ECDs with and without a neurotrophin bound. The single N-glycan on the p75 ECD provided minimal shielding and had limited interaction with the neurotrophin, although glycan-glycan contacts between the two p75 monomers may influence the stability of the receptor-neurotrophin complex. In contrast, TrkA and TrkB carry multiple N-glycans that shield the ECDs much more and, particularly for TrkB, increase the contact area between the receptor and the neurotrophin. The p75 ECD was comparatively rigid, independent of glycosylation state, likely due to its extensive network of disulfide bonds. In contrast, without glycans, the TrkA and TrkB ECDs tended to collapse inwards, sometimes obstructing the neurotrophin binding site. Glycosylation of TrkA and TrkB prevented bending of the ECD into more compact states, and instead promoted extended conformations that better accommodate neurotrophin binding. Overall, the simulations reveal distinct, receptor-specific roles of glycosylation in modulating neurotrophin receptor shielding, flexibility, and conformation, with effects on neurotrophin binding. Statement of significanceNeurotrophins are proteins that promote neuronal survival. Their binding to the extracellular domains of transmembrane receptors leads to signal transduction intracellularly. Glycosylation of some neurotrophin receptors has been reported to affect their localization and function but the mechanism is unclear. We investigate the effects of glycosylation on the structure, dynamics and binding properties of the extracellular domains of three neurotrophin receptors by molecular dynamics simulation. We identify distinct receptor-specific effects of glycosylation. In particular, we find that glycosylation of tyrosine receptor kinases prevents concealment of the neurotrophin binding site due to receptor dynamics and favors a more extended receptor conformation, thereby supporting neutrophin binding and the associated signal transduction.