Identification of a novel calpain inhibitor using phage display.
Identifieur interne : 002327 ( PubMed/Corpus ); précédent : 002326; suivant : 002328Identification of a novel calpain inhibitor using phage display.
Auteurs : Rodney P. Guttmann ; George A. Day ; Xiaohong Wang ; Kara A. BottiggiSource :
- Biochemical and biophysical research communications [ 0006-291X ] ; 2005.
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
Links to Exploration step
pubmed:15979564Le 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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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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15979564</PMID><DateCompleted><Year>2005</Year><Month>09</Month><Day>07</Day></DateCompleted><DateRevised><Year>2005</Year><Month>11</Month><Day>17</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0006-291X</ISSN><JournalIssue CitedMedium="Print"><Volume>333</Volume><Issue>4</Issue><PubDate><Year>2005</Year><Month>Aug</Month><Day>12</Day></PubDate></JournalIssue><Title>Biochemical and biophysical research communications</Title><ISOAbbreviation>Biochem. Biophys. Res. Commun.</ISOAbbreviation></Journal><ArticleTitle>Identification of a novel calpain inhibitor using phage display.</ArticleTitle><Pagination><MedlinePgn>1087-92</MedlinePgn></Pagination><Abstract><AbstractText>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. 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