Identification of a novel calpain inhibitor using phage display.
Identifieur interne : 002F03 ( Main/Exploration ); précédent : 002F02; suivant : 002F04Identification of a novel calpain inhibitor using phage display.
Auteurs : Rodney P. Guttmann [États-Unis] ; George A. Day ; Xiaohong Wang ; Kara A. BottiggiSource :
- Biochemical and biophysical research communications [ 0006-291X ] ; 2005.
Descripteurs français
- KwdFr :
- Banque de peptides, Calpain (analyse), Calpain (antagonistes et inhibiteurs), Calpain (métabolisme), Données de séquences moléculaires, Liaison aux protéines, Oligopeptides (), Oligopeptides (analyse), Oligopeptides (métabolisme), Peptides (), Peptides (analyse), Peptides (métabolisme), Sites de fixation, Séquence d'acides aminés.
- MESH :
- analyse : Calpain, Oligopeptides, Peptides.
- antagonistes et inhibiteurs : Calpain.
- métabolisme : Calpain, Oligopeptides, Peptides.
- Banque de peptides, Données de séquences moléculaires, Liaison aux protéines, Oligopeptides, Peptides, Sites de fixation, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Sequence, Binding Sites, Calpain (analysis), Calpain (antagonists & inhibitors), Calpain (metabolism), Molecular Sequence Data, Oligopeptides (analysis), Oligopeptides (chemistry), Oligopeptides (metabolism), Peptide Library, Peptides (analysis), Peptides (chemistry), Peptides (metabolism), Protein Binding.
- MESH :
- chemical , analysis : Calpain, Oligopeptides, Peptides.
- chemical , antagonists & inhibitors : Calpain.
- chemical , chemistry : Oligopeptides, Peptides.
- chemical , metabolism : Calpain, Oligopeptides, Peptides.
- Amino Acid Sequence, Binding Sites, Molecular Sequence Data, Peptide Library, Protein Binding.
Abstract
Calpains are calcium- and thiol-dependent proteases that cleave a variety of intracellular substrates. Overactivation of the calpains has been implicated in a number of diseases and conditions such as ischemic stroke indicating a need for the development of calpain inhibitors. A major problem with current calpain inhibitors has been specific targeting to calpain. To identify highly specific calpain interacting peptides, we developed a peptide-phage library screening method based on the calcium-dependent conformation change associated with calpain activation. A phage-peptide library representing greater than 2 billion expressed 12-mers was incubated with calpain I in the presence of calcium. The calcium-dependent bound phage was then eluted by addition of EGTA. After four rounds of selection we found a conserved 5-mer sequence represented by LSEAL. Synthetic LSEAL inhibited tau-calpain interaction and in vitro proteolysis of tau- and alpha-synuclein by calpains. Deletion of the portion of the tau protein containing a homologous sequence to LSEAL resulted in decreased calpain-mediated tau degradation. These data suggest that these peptides may represent novel calpastatin mimetics.
DOI: 10.1016/j.bbrc.2005.06.036
PubMed: 15979564
Affiliations:
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Le document en format XML
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Day</name></author><author><name sortKey="Wang, Xiaohong" sort="Wang, Xiaohong" uniqKey="Wang X" first="Xiaohong" last="Wang">Xiaohong Wang</name></author><author><name sortKey="Bottiggi, Kara A" sort="Bottiggi, Kara A" uniqKey="Bottiggi K" first="Kara A" last="Bottiggi">Kara A. 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Guttmann</name><affiliation wicri:level="2"><nlm:affiliation>Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. rodneyg@uky.edu</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, KY 40536</wicri:regionArea><placeName><region type="state">Kentucky</region></placeName></affiliation></author><author><name sortKey="Day, George A" sort="Day, George A" uniqKey="Day G" first="George A" last="Day">George A. Day</name></author><author><name sortKey="Wang, Xiaohong" sort="Wang, Xiaohong" uniqKey="Wang X" first="Xiaohong" last="Wang">Xiaohong Wang</name></author><author><name sortKey="Bottiggi, Kara A" sort="Bottiggi, Kara A" uniqKey="Bottiggi K" first="Kara A" last="Bottiggi">Kara A. Bottiggi</name></author></analytic><series><title level="j">Biochemical and biophysical research communications</title><idno type="ISSN">0006-291X</idno><imprint><date when="2005" type="published">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Binding Sites</term><term>Calpain (analysis)</term><term>Calpain (antagonists & inhibitors)</term><term>Calpain (metabolism)</term><term>Molecular Sequence Data</term><term>Oligopeptides (analysis)</term><term>Oligopeptides (chemistry)</term><term>Oligopeptides (metabolism)</term><term>Peptide Library</term><term>Peptides (analysis)</term><term>Peptides (chemistry)</term><term>Peptides (metabolism)</term><term>Protein Binding</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Banque de peptides</term><term>Calpain (analyse)</term><term>Calpain (antagonistes et inhibiteurs)</term><term>Calpain (métabolisme)</term><term>Données de séquences moléculaires</term><term>Liaison aux protéines</term><term>Oligopeptides ()</term><term>Oligopeptides (analyse)</term><term>Oligopeptides (métabolisme)</term><term>Peptides ()</term><term>Peptides (analyse)</term><term>Peptides (métabolisme)</term><term>Sites de fixation</term><term>Séquence d'acides aminés</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Calpain</term><term>Oligopeptides</term><term>Peptides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Calpain</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Oligopeptides</term><term>Peptides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Calpain</term><term>Oligopeptides</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Calpain</term><term>Oligopeptides</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Calpain</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Calpain</term><term>Oligopeptides</term><term>Peptides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Binding Sites</term><term>Molecular Sequence Data</term><term>Peptide Library</term><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Banque de peptides</term><term>Données de séquences moléculaires</term><term>Liaison aux protéines</term><term>Oligopeptides</term><term>Peptides</term><term>Sites de fixation</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Calpains are calcium- and thiol-dependent proteases that cleave a variety of intracellular substrates. Overactivation of the calpains has been implicated in a number of diseases and conditions such as ischemic stroke indicating a need for the development of calpain inhibitors. A major problem with current calpain inhibitors has been specific targeting to calpain. To identify highly specific calpain interacting peptides, we developed a peptide-phage library screening method based on the calcium-dependent conformation change associated with calpain activation. A phage-peptide library representing greater than 2 billion expressed 12-mers was incubated with calpain I in the presence of calcium. The calcium-dependent bound phage was then eluted by addition of EGTA. After four rounds of selection we found a conserved 5-mer sequence represented by LSEAL. Synthetic LSEAL inhibited tau-calpain interaction and in vitro proteolysis of tau- and alpha-synuclein by calpains. Deletion of the portion of the tau protein containing a homologous sequence to LSEAL resulted in decreased calpain-mediated tau degradation. These data suggest that these peptides may represent novel calpastatin mimetics.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Kentucky</li></region></list><tree><noCountry><name sortKey="Bottiggi, Kara A" sort="Bottiggi, Kara A" uniqKey="Bottiggi K" first="Kara A" last="Bottiggi">Kara A. Bottiggi</name><name sortKey="Day, George A" sort="Day, George A" uniqKey="Day G" first="George A" last="Day">George A. Day</name><name sortKey="Wang, Xiaohong" sort="Wang, Xiaohong" uniqKey="Wang X" first="Xiaohong" last="Wang">Xiaohong Wang</name></noCountry><country name="États-Unis"><region name="Kentucky"><name sortKey="Guttmann, Rodney P" sort="Guttmann, Rodney P" uniqKey="Guttmann R" first="Rodney P" last="Guttmann">Rodney P. 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