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Orexin A, an amphipathic α-helical neuropeptide involved in pleiotropic functions in the nervous and immune systems: Synthetic approach and biophysical studies of the membrane-bound state. | LitMetric

AI Article Synopsis

  • This research focuses on orexin A (OXA), a neuropeptide with key roles in functions such as sleep regulation, energy balance, and neuroprotection, that interacts with neural and immune cell membranes.
  • The study introduces a synthetic method to produce isotopically-labeled OXA, allowing detailed investigation of its structure and activity in a membrane environment using techniques like NMR and surface plasmon resonance.
  • Findings reveal that OXA exhibits strong interactions with phospholipid membranes, improves its α-helical content upon binding, and identifies critical structural orientations that may lead to new therapeutic approaches for treating conditions like neuroinflammation and Alzheimer's disease.

Article Abstract

This research reports on the membrane interactions of orexin A (OXA), an α-helical and amphipathic neuropeptide that contains 33 residues and two disulfide bonds in the N-terminal region. OXA, which activates the orexins 1 and 2 receptors in neural and immune cell membranes, has essential pleiotropic physiological effects, including at the levels of arousal, sleep/wakefulness, energy balance, neuroprotection, lipid signaling, the inflammatory response, and pain. As a result, the orexin system has become a prominent target to treat diseases such as sleep disorders, drug addiction, and inflammation. While the high-resolution structure of OXA has been investigated in water and bound to micelles, there is a lack of information about its conformation bound to phospholipid membranes and its receptors. NMR is a powerful method to investigate peptide structures in a membrane environment. To facilitate the NMR structural studies of OXA exposed to membranes, we present a novel synthetic scheme, leading to the production of isotopically-labeled material at high purity. A receptor activation assay shows that the N-labeled peptide is biologically active. Biophysical studies are performed using surface plasmon resonance, circular dichroism, and NMR to investigate the interactions of OXA with phospholipid bilayers. The results demonstrate a strong interaction between the peptide and phospholipids, an increase in α-helical content upon membrane binding, and an in-plane orientation of the C-terminal region critical to function. This new knowledge about structure-activity relationships in OXA could inspire the design of novel therapeutics that leverage the anti-inflammatory and neuro-protective functions of OXA, and therefore could help address neuroinflammation, a major issue associated with neurological disorders such as Alzheimer's disease.

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Source
http://dx.doi.org/10.1016/j.bpc.2023.107007DOI Listing

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