title: The tachykinin peptide neurokinin B binds copper(I) and silver(I) and undergoes quasi-reversible electrochemistry: towards a new function for the peptide in the brain.
abstract: The tachykinin neuropeptide family, which includes substance P and neurokinin B, is involved in a wide array of biological functions. Among these is the ability to protect against the neurotoxic processes in Alzheimer's Disease, but the mechanisms driving neuroprotection remain unclear. Dysregulation of metal ions, particularly copper, iron and zinc is a common feature of Alzheimer's Disease, and other amyloidogenic disorders. Copper is known to be released from neurons and recent work has shown that some tachykinins can bind Cu(II) ions, and that neurokinin B can inhibit copper uptake into astrocytes. We have now examined whether neurokinin B is capable of binding Cu(I), which is predicted to be available in the synapse. Using a combination of spectroscopic techniques including cyclic voltammetry and magnetic resonance we show that neurokinin B can bind Cu(I) either directly from added CuCl or by reduction of Cu(II)-bound neurokinin B. The results showed that the Cu(I) binding site differs greatly to that of Cu(II) and involves thioether coordination via Met2 and Met10 and an imidazole nitrogen ligand from His3. The Cu(I) coordination is also different to the site adopted by Ag(I). During changes in oxidation state, copper remains bound to neurokinin B despite large changes to the inner coordination sphere. We predict that neurokinin B may be involved in synaptic copper homeostasis.
authors.affiliation: The School of Science and Health, The University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia.
authors.forename: Aidan B
authors.initials: AB
authors.lastname: Grosas
authors.affiliation: School of Chemical and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia.
authors.forename: Palraj
authors.initials: P
authors.lastname: Kalimuthu
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Smith
authors.affiliation: The School of Science and Health, The University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Williams
authors.affiliation: The School of Science and Health, The University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Millar
authors.affiliation: School of Chemical and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.affiliation: The School of Science and Health, The University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia. Electronic address: c.jones@uws.edu.au.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Jones
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D004563:Electrochemistry / Q000379:methods; D006801:Humans; D015288:Neurokinin A / Q000378:metabolism; D015287:Neurokinin B / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D012834:Silver / Q000378:metabolism*; D015320:Tachykinins / Q000378:metabolism*
chemical_list: D015320:Tachykinins; D012834:Silver; D003300:Copper; D015288:Neurokinin A; D015287:Neurokinin B
keywords: Copper; Copper homeostasis; Metal; Neurokinin B; Neuropeptide; Peptide; Protein; Synapse; Tachykinin