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The binding of zinc and copper ions to nerve growth factor is differentially affected by pH: implications for cerebral acidosis
Author(s) -
Ross Gregory M.,
Shamovsky Igor L.,
Woo Sang B.,
Post Joan I.,
Vrkljan Philip N.,
Lawrance Gail,
Solc Mark,
Dostaler Suzanne M.,
Neet Kenneth E.,
Riopelle Richard J.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00427.x
Subject(s) - nerve growth factor , tropomyosin receptor kinase a , chemistry , histidine , neurotrophin , acidosis , tyrosine , biochemistry , biophysics , receptor , endocrinology , biology , amino acid
It has recently been shown that transition metal cations Zn 2+ and Cu 2+ bind to histidine residues of nerve growth factor (NGF) and other neurotrophins (a family of proteins important for neuronal survival) leading to their inactivation. Experimental data and theoretical considerations indicate that transition metal cations may destabilize the ionic form of histidine residues within proteins, thereby decreasing their p K a values. Because the release of transition metal cations and acidification of the local environment represent important events associated with brain injury, the ability of Zn 2+ and Cu 2+ to bind to neurotrophins in acidic conditions may alter neuronal death following stroke or as a result of traumatic injury. To test the hypothesis that metal ion binding to neurotrophins is influenced by pH, the effects of Zn 2+ and Cu 2+ on NGF conformation, receptor binding and NGF tyrosine kinase (trkA) receptor signal transduction were examined under conditions mimicking cerebral acidosis (pH range 5.5–7.4). The inhibitory effect of Zn 2+ on biological activities of NGF is lost under acidic conditions. Conversely, the binding of Cu 2+ to NGF is relatively independent of pH changes within the studied range. These data demonstrate that Cu 2+ has greater binding affinity to NGF than Zn 2+ at reduced pH, consistent with the higher affinity of Cu 2+ for histidine residues. These findings suggest that cerebral acidosis associated with stroke or traumatic brain injury could neutralize the Zn 2+ ‐mediated inactivation of NGF, whereas corresponding pH changes would have little or no influence on the inhibitory effects of Cu 2+ . The importance of His84 of NGF for transition metal cation binding is demonstrated, confirming the involvement of this residue in metal ion coordination.