Illuminating the role of the intrinsically disordered regions of pro-neurotrophins and their interacting cartography with ligands and receptors by integrative structural biology with hybrid methods

Nerve growth factor (NGF), the prototypical neurotrophic factor, is involved in the maintenance and growth of neuronal populations, whereas its precursor, proNGF, is involved in neuronal apoptosis. The NGF/proNGF ratio is strictly controlled in vivo and has a pivotal role in neurodegeneration. Binding of NGF or proNGF to TrkA, p75^NTR, and VP10p receptors triggers complex intracellular signalling pathways that can be modulated by Small Endogenous Ligands (SELs). The role of the ligands in these processes remains poorly understood because of the lack of architectural details on the pro-neurotrophin pro-peptide, predicted to be an Intrinsically Disordered Region (IDR). This proposal aims at widening the molecular understanding of proNGF biological responses, through an integrative structural biology approach. The NMR spectral assignment of proNGF represents a sine qua non milestone for biophysical studies aimed to unravel the molecular determinants of SELs in the modulation of receptors’ binding in physiological versus pathological conditions. The optimization of a workflow for proNGF would allow to extend it to different ligands, as well as to other pro-neurotrophins of the family.