Analysis of Interaction between Cellular Prion Protein (PrPC) and Irisin

Exerkines are molecules released into the bloodstream by muscle tissue in response to contraction during physical exercise, possessing beneficial effects on various organs and tissues. Among these is irisin, a myokine cleaved from the FNDC5 protein (Fibronectin type III domain-containing protein 5). Previous studies have shown the neuroprotective effects of irisin in rescuing memory and synaptic plasticity in models of Alzheimer's disease (AD) [1]. These neuroprotective effects are mediated, at least in part, by irisin-induced activation of intracellular signaling pathways that lead to the generation of neuroprotective molecules, and this signaling can occur through interaction with receptors present on the neuronal membrane, such as integrin αV/β5; however, other cell surface proteins may also participate in modulating the biological effects triggered by the myokine [2]. One of these receptors may be the Cellular Prion Protein (PrP^C), which, in a physiological context, interacts with signaling pathways capable of generating neuroprotective mediators (also activated by irisin), such as the MAPKs/ERK pathway and cAMP signaling [3]. Furthermore, PrP^C interacts with various molecules such as Fibronectin [4]. Given that irisin is cleaved from a protein containing a Fibronectin domain, we hypothesize that PrP^C may be a receptor for irisin and that this interaction is responsible for mediating the neuroprotective effect exerted by the myokine. Applying computational tools, such as Molecular Docking and Molecular Dynamics simulations, the study sought to obtain a stable complex and subsequently map the interaction interface between PrP^C and irisin. Through the application of Quantum Mechanics (QM) methods, residues present at the reactivity interface involved in intermolecular interactions and charge transfer were identified. The combination of classical and quantum computational methods allowed for the determination of a stable complex and an interaction surface involving residues present in the N-terminal region of PrP^C (domain 90-125) interacting with residues in domains 54–62 and 72 to 110 of irisin. These findings may contribute to the design of irisin-derived peptides with the capacity to bind to PrP^C and activate neuroprotective signaling pathways.