Intracerebral hormone peptide Orexin-A
Human (Homo sapiens)
Orexin-A and orexin-B, also called hypocretin-1 and hypocretin-2, respectively, are neuropeptides, which are generated through the proteolytic cleavage of a common precursor, prepro-orexin or prepro-hypocretin, composed of 131 amino acid residues. Orexins-A and -B bind to two mutually closely related (64% homology) orphan (of which ligand is unknown) G protein-coupled receptors (GPCRs), named orexin-1 (OX1R) and orexin-2 (OX2R) receptors to activate them. The messenger-RNA of the precursor is specifically expressed in the lateral hypothalamus area (LHA), known as a feeding center. Since intracerebroventricular administration of orexins stimulates feeding in rats and mice, and orexins are colocalized with other orexigenic peptides including dynorphin and galanin, orexins are thought to function as potent orexigenic peptides (the Greek word "orexis" meaning appetite). Furthermore, orexin-knockout mice exhibit a syndrome similar to human narcolepsy. Therefore, it is suggested that orexins play an important role in regulating feeding and sleep-wakefulness by modulating energy metabolism.
The sequences and functions of orexins-A and B are similar to each other, but the high sequence homology (68%) is limited in their C-terminal half regions (Figure).
The sequence of the N-terminal half region of orexin-A, containing two disulfide bonds, is very different from that of orexin-B. According to the structure of orexin-A, it has a compact conformation in the N-terminal half region, which contains a short helix and is fixed by the two disulfide bonds, and a helix-turn-helix conformation in the remaining C-terminal half region. The C-terminal half region has both hydrophobic and hydrophilic residues, which exist on the separate surfaces to provide an amphipathic character in helices I and II. The nine residues on the hydrophobic surface are well conserved also in orexin-B, and it was reported that the substitution of each of them with alanine resulted in a significant drop in the functional potency at the receptors. Therefore, it is suggested that they form the surface responsible for the main hydrophobic interaction with the receptors. On the other hand, the residues on the hydrophilic surface, together with the hydrophilic residues in the N-terminal half region that form a cluster, are known to make only small contributions to the binding to the receptors through similar alanine-scan experiments. However, since the structure of orexin-A show that large conformational and electrostatical differences between orexins-A and B are rather concentrated in the N-terminal half regions, the region of orexin-A may be important for the preference for orexin-A of OX1R.
Protein Data Bank (PDB)
author: Takahisa Ikegami