Alterations in secondary structure and binding affinity from mutations in the interleukin-1 receptor antagonist

Abstract

AbstractDeficiency of Interleukin-1 receptor antagonist (DIRA) is a rare autosomal recessive autoinflammatory disorder that occurs during the neonatal period, manifesting a spectrum of symptoms including but not limited to osteomyelitis and pustulosis. This disease results from loss-of-function mutations in theIL1RNgene, encoding the IL-1 receptor antagonist (IL-1Ra). The dysfunction of IL-1Ra may arise from two mechanisms: (i) disruptions in the folding of its secondary structure, and (ii) impaired binding to its receptor, IL-1 receptor type 1. However, limited information exists detailing broad alterations in structure and binding affinity of known IL-1Ra variants. Herein, we used a validated protein prediction model to visualize 15 unique variants, and subsequently performed a structural analysis to elucidate the mutational impacts on secondary structure and binding affinity. Our analyses revealed reduced affinity at the 5 critical binding sites (W16, Q20, Y34, Q36, and Y147) along with missing secondary structures (β-sheets, α-helices) among the variants.HighlightsStructural analyses revealed reduced binding affinity resulting from impacts in critical binding sites of IL-1Ra.This is the first study broadly evaluating the mutational impacts on structure and binding affinity of IL-1Ra.A validatedin silicoprotocol was used to predict structural alterations of the IL-1Ra variants.