The NGF R100W Mutation, Associated with Hereditary Sensory Autonomic Neuropathy Type V, Specifically Affects the Binding Energetic Landscapes of NGF and of Its Precursor proNGF and p75NTR

Abstract

Nerve Growth Factor (NGF), the prototype of the neurotrophin family, stimulates morphological differentiation and regulates neuronal gene expression by binding to TrkA and p75NTR receptors. It plays a critical role in maintaining the function and phenotype of peripheral sensory and sympathetic neurons and in mediating pain transmission and perception during adulthood. A point mutation in the NGFB gene (leading to the amino acid substitution R100W) is responsible for Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), leading to a congenital pain insensitivity with no clear cognitive impairments, but with alterations in the NGF/proNGF balance. The available crystal structures of the p75NTR/NGF and 2p75NTR/proNGF complexes offer a starting point for Molecular Dynamics (MD) simulations in order to capture the impact of the R100W mutation on their binding energetic landscapes and to unveil the molecular determinants that trigger their different physiological and pathological outcomes. The present in silico studies highlight that the stability and the binding energetic fingerprints in the 2p75NTR/proNGF complex is not affected by R100W mutation, which on the contrary, deeply affects the energetic landscape, and thus the stability in the p75NTR/NGF complex. Overall, these findings present insights into the structural basis of the molecular mechanisms beyond the clinical manifestations of HSAN V patients.