Essential Role of Histidine for Rapid Copper(II)-Mediated Disassembly of Neurokinin B Amyloid

Abstract

Neurokinin B is a tachykinin peptide involved in a diverse range of neuronal functions. It rapidly forms an amyloid, which is considered physiologically important for efficient packing into dense core secretory vesicles within hypothalamic neurons. Disassembly of the amyloid is thought to require the presence of copper ions, which interact with histidine at the third position in the peptide sequence. However, it is unclear how the histidine is involved in the amyloid structure and why copper coordination can trigger disassembly. In this work, we demonstrate that histidine contributes to the amyloid structure via π-stacking interactions with nearby phenylalanine residues. The ability of neurokinin B to form an amyloid is dependent on any aromatic residue at the third position in the sequence; however, only the presence of histidine leads to both amyloid formation and rapid copper-induced disassembly.

Structural Stabilization of Clinically Oriented Oligomeric Proteins During their Transit through Synthetic Secretory Amyloids

“…[39] On the other hand, cationic Zn (as used here) initiates the oligomerization of histidine-containing proteins (such as prolactin [40] and GH [3] ), while dilution (or chelation [3,41] ) of this metal in the media promotes protein leakage from amyloids. Also, ionic cooper triggers disassembly of neurokinin B functional amyloids, [42] probably by blocking the imidazole group from His 3 , a critical residue in the assembly (and disassembly) of this neuropeptide as secretory amyloids. [42][43][44] How organic signals induce the disassembly of secretory amyloids for protein hormone release, upon functional needs, is not yet clear.…”

“…Also, ionic cooper triggers disassembly of neurokinin B functional amyloids, [42] probably by blocking the imidazole group from His 3 , a critical residue in the assembly (and disassembly) of this neuropeptide as secretory amyloids. [42][43][44] How organic signals induce the disassembly of secretory amyloids for protein hormone release, upon functional needs, is not yet clear. An interesting attempt in this regard is that done regarding the secretion of GH from the pituitary gland, [38] whose homeostasis might require dozens of kinases and phosphatases.…”

“…Also, ionic cooper triggers disassembly of neurokinin B functional amyloids, [ 42 ] probably by blocking the imidazole group from His 3 , a critical residue in the assembly (and disassembly) of this neuropeptide as secretory amyloids. [ 42 , 43 , 44 ]…”