The binding of zinc and copper ions to nerve growth factor is differentially affected by pH: implications for cerebral acidosis

It has recently been shown that transition metal cations Zn2+ and Cu2+ 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...

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Veröffentlicht in:Journal of neurochemistry 2001-08, Vol.78 (3), p.515-523
Hauptverfasser: 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.
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container_end_page 523
container_issue 3
container_start_page 515
container_title Journal of neurochemistry
container_volume 78
creator 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.
description It has recently been shown that transition metal cations Zn2+ and Cu2+ 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 pKa values. Because the release of transition metal cations and acidification of the local environment represent important events associated with brain injury, the ability of Zn2+ and Cu2+ 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 Zn2+ and Cu2+ 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 Zn2+ on biological activities of NGF is lost under acidic conditions. Conversely, the binding of Cu2+ to NGF is relatively independent of pH changes within the studied range. These data demonstrate that Cu2+ has greater binding affinity to NGF than Zn2+ at reduced pH, consistent with the higher affinity of Cu2+ for histidine residues. These findings suggest that cerebral acidosis associated with stroke or traumatic brain injury could neutralize the Zn2+‐mediated inactivation of NGF, whereas corresponding pH changes would have little or no influence on the inhibitory effects of Cu2+. The importance of His84 of NGF for transition metal cation binding is demonstrated, confirming the involvement of this residue in metal ion coordination.
doi_str_mv 10.1046/j.1471-4159.2001.00427.x
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Experimental data and theoretical considerations indicate that transition metal cations may destabilize the ionic form of histidine residues within proteins, thereby decreasing their pKa values. Because the release of transition metal cations and acidification of the local environment represent important events associated with brain injury, the ability of Zn2+ and Cu2+ 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 Zn2+ and Cu2+ 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 Zn2+ on biological activities of NGF is lost under acidic conditions. Conversely, the binding of Cu2+ to NGF is relatively independent of pH changes within the studied range. These data demonstrate that Cu2+ has greater binding affinity to NGF than Zn2+ at reduced pH, consistent with the higher affinity of Cu2+ for histidine residues. These findings suggest that cerebral acidosis associated with stroke or traumatic brain injury could neutralize the Zn2+‐mediated inactivation of NGF, whereas corresponding pH changes would have little or no influence on the inhibitory effects of Cu2+. The importance of His84 of NGF for transition metal cation binding is demonstrated, confirming the involvement of this residue in metal ion coordination.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1046/j.1471-4159.2001.00427.x</identifier><identifier>PMID: 11483654</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Acidosis - metabolism ; Animals ; Autoradiography ; Biological and medical sciences ; Brain Diseases - metabolism ; Copper - metabolism ; Humans ; Hydrogen-Ion Concentration ; Immunoblotting ; Injuries of the nervous system and the skull. Diseases due to physical agents ; Iodine Radioisotopes - metabolism ; Kinetics ; Medical sciences ; metalloproteins ; Mice ; Nerve Growth Factor - genetics ; Nerve Growth Factor - metabolism ; neurotrophin ; NGF ; PC12 Cells ; Phosphorylation ; Protein Binding ; Protein Conformation ; Rats ; Receptor, Nerve Growth Factor - chemistry ; Receptor, Nerve Growth Factor - isolation &amp; purification ; Receptor, Nerve Growth Factor - metabolism ; Receptor, trkA - chemistry ; Receptor, trkA - metabolism ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Signal Transduction ; stroke ; Surface Plasmon Resonance ; transition metal cations ; Traumas. 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Experimental data and theoretical considerations indicate that transition metal cations may destabilize the ionic form of histidine residues within proteins, thereby decreasing their pKa values. Because the release of transition metal cations and acidification of the local environment represent important events associated with brain injury, the ability of Zn2+ and Cu2+ 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 Zn2+ and Cu2+ 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 Zn2+ on biological activities of NGF is lost under acidic conditions. Conversely, the binding of Cu2+ to NGF is relatively independent of pH changes within the studied range. These data demonstrate that Cu2+ has greater binding affinity to NGF than Zn2+ at reduced pH, consistent with the higher affinity of Cu2+ for histidine residues. These findings suggest that cerebral acidosis associated with stroke or traumatic brain injury could neutralize the Zn2+‐mediated inactivation of NGF, whereas corresponding pH changes would have little or no influence on the inhibitory effects of Cu2+. The importance of His84 of NGF for transition metal cation binding is demonstrated, confirming the involvement of this residue in metal ion coordination.</description><subject>Acidosis - metabolism</subject><subject>Animals</subject><subject>Autoradiography</subject><subject>Biological and medical sciences</subject><subject>Brain Diseases - metabolism</subject><subject>Copper - metabolism</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Immunoblotting</subject><subject>Injuries of the nervous system and the skull. Diseases due to physical agents</subject><subject>Iodine Radioisotopes - metabolism</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>metalloproteins</subject><subject>Mice</subject><subject>Nerve Growth Factor - genetics</subject><subject>Nerve Growth Factor - metabolism</subject><subject>neurotrophin</subject><subject>NGF</subject><subject>PC12 Cells</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Rats</subject><subject>Receptor, Nerve Growth Factor - chemistry</subject><subject>Receptor, Nerve Growth Factor - isolation &amp; purification</subject><subject>Receptor, Nerve Growth Factor - metabolism</subject><subject>Receptor, trkA - chemistry</subject><subject>Receptor, trkA - metabolism</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>stroke</subject><subject>Surface Plasmon Resonance</subject><subject>transition metal cations</subject><subject>Traumas. Diseases due to physical agents</subject><subject>traumatic brain injury</subject><subject>Zinc - metabolism</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS1ERYfCKyBvYJfgG_8liA0aUQqqYFPWluOf1qNMHOwM7XTDq-N0RnRZVrZ1vnOvpQ8hDKQGwsT7TQ1MQsWAd3VDCNSEsEbWd8_Q6l_wHK0IaZqKlugUvcx5U0DBBLxApwCspYKzFfpzdeNwH0YbxmscPb4Po8F6tNjEaXIJhzhmPEc8uvTb4esUb-cb7LWZY8kytsF7l9w4Bz0Me6zLy8zO4n6Pp4sPOGynIRg9P0zxpWIK3Cc9YG2CjTnkV-jE6yG718fzDP08_3y1vqguf3z5uv50WRnWcFl1TUutJNy1hDPegtSUd7ITWnTGciqMaDvwALLpecs98cZwazRY5ywRYOgZeneYO6X4a-fyrLYhGzcMenRxl5UEwgUh9EkQWuhEJxewPYAmxZyT82pKYavTXgFRiyW1UYsMtchQiyX1YEndleqb445dv3X2sXjUUoC3R0Bnowef9GhCfuQY6SjjTeE-HrjbMLj9f39Affu-Lhf6Fz_lraY</recordid><startdate>200108</startdate><enddate>200108</enddate><creator>Ross, Gregory M.</creator><creator>Shamovsky, Igor L.</creator><creator>Woo, Sang B.</creator><creator>Post, Joan I.</creator><creator>Vrkljan, Philip N.</creator><creator>Lawrance, Gail</creator><creator>Solc, Mark</creator><creator>Dostaler, Suzanne M.</creator><creator>Neet, Kenneth E.</creator><creator>Riopelle, Richard J.</creator><general>Blackwell Science Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>200108</creationdate><title>The binding of zinc and copper ions to nerve growth factor is differentially affected by pH: implications for cerebral acidosis</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4257-9283d705e80545817a359796a69cd536c6891f1172b585f0fcc5dca1deed061c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Acidosis - metabolism</topic><topic>Animals</topic><topic>Autoradiography</topic><topic>Biological and medical sciences</topic><topic>Brain Diseases - metabolism</topic><topic>Copper - metabolism</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Immunoblotting</topic><topic>Injuries of the nervous system and the skull. Diseases due to physical agents</topic><topic>Iodine Radioisotopes - metabolism</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>metalloproteins</topic><topic>Mice</topic><topic>Nerve Growth Factor - genetics</topic><topic>Nerve Growth Factor - metabolism</topic><topic>neurotrophin</topic><topic>NGF</topic><topic>PC12 Cells</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Rats</topic><topic>Receptor, Nerve Growth Factor - chemistry</topic><topic>Receptor, Nerve Growth Factor - isolation &amp; purification</topic><topic>Receptor, Nerve Growth Factor - metabolism</topic><topic>Receptor, trkA - chemistry</topic><topic>Receptor, trkA - metabolism</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>stroke</topic><topic>Surface Plasmon Resonance</topic><topic>transition metal cations</topic><topic>Traumas. Diseases due to physical agents</topic><topic>traumatic brain injury</topic><topic>Zinc - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ross, Gregory M.</creatorcontrib><creatorcontrib>Shamovsky, Igor L.</creatorcontrib><creatorcontrib>Woo, Sang B.</creatorcontrib><creatorcontrib>Post, Joan I.</creatorcontrib><creatorcontrib>Vrkljan, Philip N.</creatorcontrib><creatorcontrib>Lawrance, Gail</creatorcontrib><creatorcontrib>Solc, Mark</creatorcontrib><creatorcontrib>Dostaler, Suzanne M.</creatorcontrib><creatorcontrib>Neet, Kenneth E.</creatorcontrib><creatorcontrib>Riopelle, Richard J.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ross, Gregory M.</au><au>Shamovsky, Igor L.</au><au>Woo, Sang B.</au><au>Post, Joan I.</au><au>Vrkljan, Philip N.</au><au>Lawrance, Gail</au><au>Solc, Mark</au><au>Dostaler, Suzanne M.</au><au>Neet, Kenneth E.</au><au>Riopelle, Richard J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The binding of zinc and copper ions to nerve growth factor is differentially affected by pH: implications for cerebral acidosis</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2001-08</date><risdate>2001</risdate><volume>78</volume><issue>3</issue><spage>515</spage><epage>523</epage><pages>515-523</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>It has recently been shown that transition metal cations Zn2+ and Cu2+ 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 pKa values. Because the release of transition metal cations and acidification of the local environment represent important events associated with brain injury, the ability of Zn2+ and Cu2+ 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 Zn2+ and Cu2+ 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 Zn2+ on biological activities of NGF is lost under acidic conditions. Conversely, the binding of Cu2+ to NGF is relatively independent of pH changes within the studied range. These data demonstrate that Cu2+ has greater binding affinity to NGF than Zn2+ at reduced pH, consistent with the higher affinity of Cu2+ for histidine residues. These findings suggest that cerebral acidosis associated with stroke or traumatic brain injury could neutralize the Zn2+‐mediated inactivation of NGF, whereas corresponding pH changes would have little or no influence on the inhibitory effects of Cu2+. The importance of His84 of NGF for transition metal cation binding is demonstrated, confirming the involvement of this residue in metal ion coordination.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>11483654</pmid><doi>10.1046/j.1471-4159.2001.00427.x</doi><tpages>9</tpages></addata></record>
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source MEDLINE; Access via Wiley Online Library; IngentaConnect Free/Open Access Journals; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection); Free Full-Text Journals in Chemistry
subjects Acidosis - metabolism
Animals
Autoradiography
Biological and medical sciences
Brain Diseases - metabolism
Copper - metabolism
Humans
Hydrogen-Ion Concentration
Immunoblotting
Injuries of the nervous system and the skull. Diseases due to physical agents
Iodine Radioisotopes - metabolism
Kinetics
Medical sciences
metalloproteins
Mice
Nerve Growth Factor - genetics
Nerve Growth Factor - metabolism
neurotrophin
NGF
PC12 Cells
Phosphorylation
Protein Binding
Protein Conformation
Rats
Receptor, Nerve Growth Factor - chemistry
Receptor, Nerve Growth Factor - isolation & purification
Receptor, Nerve Growth Factor - metabolism
Receptor, trkA - chemistry
Receptor, trkA - metabolism
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Signal Transduction
stroke
Surface Plasmon Resonance
transition metal cations
Traumas. Diseases due to physical agents
traumatic brain injury
Zinc - metabolism
title The binding of zinc and copper ions to nerve growth factor is differentially affected by pH: implications for cerebral acidosis
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