Combinatorial library of improved peptide aptamers, CLIPs to inhibit RAGE signal transduction in mammalian cells
Peptide aptamers are small proteins containing a randomized peptide sequence embedded into a stable protein scaffold, such as Thioredoxin. We developed a robust method for building a Combinatorial Library of Improved Peptide aptamers (CLIPs) of high complexity, containing ≥3×10(10) independent clone...
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| Veröffentlicht in: | PloS one 2013-06, Vol.8 (6), p.e65180-e65180 |
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| creator | Reverdatto, Sergey Rai, Vivek Xue, Jing Burz, David S Schmidt, Ann Marie Shekhtman, Alexander |
| description | Peptide aptamers are small proteins containing a randomized peptide sequence embedded into a stable protein scaffold, such as Thioredoxin. We developed a robust method for building a Combinatorial Library of Improved Peptide aptamers (CLIPs) of high complexity, containing ≥3×10(10) independent clones, to be used as a molecular tool in the study of biological pathways. The Thioredoxin scaffold was modified to increase solubility and eliminate aggregation of the peptide aptamers. The CLIPs was used in a yeast two-hybrid screen to identify peptide aptamers that bind to various domains of the Receptor for Advanced Glycation End products (RAGE). NMR spectroscopy was used to identify interaction surfaces between the peptide aptamers and RAGE domains. Cellular functional assays revealed that in addition to directly interfering with known binding sites, peptide aptamer binding distal to ligand sites also inhibits RAGE ligand-induced signal transduction. This finding underscores the potential of using CLIPs to select allosteric inhibitors of biological targets. |
| doi_str_mv | 10.1371/journal.pone.0065180 |
| format | Article |
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We developed a robust method for building a Combinatorial Library of Improved Peptide aptamers (CLIPs) of high complexity, containing ≥3×10(10) independent clones, to be used as a molecular tool in the study of biological pathways. The Thioredoxin scaffold was modified to increase solubility and eliminate aggregation of the peptide aptamers. The CLIPs was used in a yeast two-hybrid screen to identify peptide aptamers that bind to various domains of the Receptor for Advanced Glycation End products (RAGE). NMR spectroscopy was used to identify interaction surfaces between the peptide aptamers and RAGE domains. Cellular functional assays revealed that in addition to directly interfering with known binding sites, peptide aptamer binding distal to ligand sites also inhibits RAGE ligand-induced signal transduction. This finding underscores the potential of using CLIPs to select allosteric inhibitors of biological targets.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0065180</identifier><identifier>PMID: 23785412</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Advanced glycosylation end products ; Allosteric properties ; Animals ; Aptamers ; Aptamers, Peptide - chemistry ; Aptamers, Peptide - pharmacology ; Binding sites ; Biochemistry ; Biology ; Cell Line ; Cells (Biology) ; Cellular signal transduction ; Chemistry ; Clips ; Combinatorial analysis ; E coli ; Escherichia coli ; Glycosylation ; Ligands ; Magnetic resonance spectroscopy ; Male ; Mammalian cells ; Medical screening ; Mice ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; NMR ; NMR spectroscopy ; Nuclear magnetic resonance ; Nuclear magnetic resonance spectroscopy ; Peptide Library ; Peptides ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Proteins ; Rats ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic - antagonists & inhibitors ; Receptors, Immunologic - chemistry ; Signal transduction ; Signal Transduction - drug effects ; Solubility ; Spectroscopy ; Thioredoxin ; Thioredoxins ; Thioredoxins - chemistry ; Thioredoxins - genetics ; Thioredoxins - metabolism ; Two-Hybrid System Techniques ; Yeast</subject><ispartof>PloS one, 2013-06, Vol.8 (6), p.e65180-e65180</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Reverdatto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Reverdatto et al 2013 Reverdatto et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-be08ba964732bc8f79c85135051b0a46b436ad1e72ab4718f20f1bcd2f7931de3</citedby><cites>FETCH-LOGICAL-c692t-be08ba964732bc8f79c85135051b0a46b436ad1e72ab4718f20f1bcd2f7931de3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681763/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681763/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79472,79473</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23785412$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Verma, Chandra</contributor><creatorcontrib>Reverdatto, Sergey</creatorcontrib><creatorcontrib>Rai, Vivek</creatorcontrib><creatorcontrib>Xue, Jing</creatorcontrib><creatorcontrib>Burz, David S</creatorcontrib><creatorcontrib>Schmidt, Ann Marie</creatorcontrib><creatorcontrib>Shekhtman, Alexander</creatorcontrib><title>Combinatorial library of improved peptide aptamers, CLIPs to inhibit RAGE signal transduction in mammalian cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Peptide aptamers are small proteins containing a randomized peptide sequence embedded into a stable protein scaffold, such as Thioredoxin. We developed a robust method for building a Combinatorial Library of Improved Peptide aptamers (CLIPs) of high complexity, containing ≥3×10(10) independent clones, to be used as a molecular tool in the study of biological pathways. The Thioredoxin scaffold was modified to increase solubility and eliminate aggregation of the peptide aptamers. The CLIPs was used in a yeast two-hybrid screen to identify peptide aptamers that bind to various domains of the Receptor for Advanced Glycation End products (RAGE). NMR spectroscopy was used to identify interaction surfaces between the peptide aptamers and RAGE domains. Cellular functional assays revealed that in addition to directly interfering with known binding sites, peptide aptamer binding distal to ligand sites also inhibits RAGE ligand-induced signal transduction. This finding underscores the potential of using CLIPs to select allosteric inhibitors of biological targets.</description><subject>Advanced glycosylation end products</subject><subject>Allosteric properties</subject><subject>Animals</subject><subject>Aptamers</subject><subject>Aptamers, Peptide - chemistry</subject><subject>Aptamers, Peptide - pharmacology</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Cell Line</subject><subject>Cells (Biology)</subject><subject>Cellular signal transduction</subject><subject>Chemistry</subject><subject>Clips</subject><subject>Combinatorial analysis</subject><subject>E coli</subject><subject>Escherichia coli</subject><subject>Glycosylation</subject><subject>Ligands</subject><subject>Magnetic resonance spectroscopy</subject><subject>Male</subject><subject>Mammalian cells</subject><subject>Medical screening</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>NMR</subject><subject>NMR spectroscopy</subject><subject>Nuclear magnetic resonance</subject><subject>Nuclear magnetic resonance spectroscopy</subject><subject>Peptide Library</subject><subject>Peptides</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Proteins</subject><subject>Rats</subject><subject>Receptor for Advanced Glycation End Products</subject><subject>Receptors, Immunologic - antagonists & inhibitors</subject><subject>Receptors, Immunologic - chemistry</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Solubility</subject><subject>Spectroscopy</subject><subject>Thioredoxin</subject><subject>Thioredoxins</subject><subject>Thioredoxins - chemistry</subject><subject>Thioredoxins - genetics</subject><subject>Thioredoxins - metabolism</subject><subject>Two-Hybrid System Techniques</subject><subject>Yeast</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QDgig4Y76atjfCMKzrwMLK-nEbTtN0JkPbdJN00X9v6nSXqeyF9CIlec57ct6ckyQvCV4SlpGPezu4Dpplbzu9xFikJMePklNSMLoQFLPHR_8nyTPv9xinLBfiaXJCWZannNDTpF_btjQdBOsMNKgxpQP3G9kambZ39lZXqNd9MJVG0AdotfMf0Ppy89WjYJHpdqY0AV2vLs6RN9t4HxQcdL4aVDC2iwBqoW2hMdAhpZvGP0-e1NB4_WJaz5Ifn8-_r78sLq8uNuvV5UKJgoZFqXFeQiF4xmip8jorVJ4SluKUlBi4KDkTUBGdUSh5RvKa4pqUqqKRZKTS7Cx5fdDtG-vlZJaXhIks5SnPaCQ2B6KysJe9M22sXFow8u-GdVsJLhjVaMlrmuYVpZQA46rWOS4AlOAF5YBzTaLWpynbULa6UrqLNjQz0flJZ3Zya28lEznJBIsC7yYBZ28G7YNsjR8Ng07bYbx3hiMmijHXm3_Qh6ubqC3EAkxX25hXjaJyxbOcFiQ2TKSWD1Dxq3RrVOys2sT9WcD7WUBkgv4VtjB4Lzffrv-fvfo5Z98esTsNTdh52wxjF_k5yA-gctZ7p-t7kwkeXSJ3bshxMOQ0GDHs1fED3QfdTQL7A0UiCEs</recordid><startdate>20130613</startdate><enddate>20130613</enddate><creator>Reverdatto, Sergey</creator><creator>Rai, Vivek</creator><creator>Xue, Jing</creator><creator>Burz, David S</creator><creator>Schmidt, Ann Marie</creator><creator>Shekhtman, Alexander</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130613</creationdate><title>Combinatorial library of improved peptide aptamers, CLIPs to inhibit RAGE signal transduction in mammalian cells</title><author>Reverdatto, Sergey ; Rai, Vivek ; Xue, Jing ; Burz, David S ; Schmidt, Ann Marie ; Shekhtman, Alexander</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-be08ba964732bc8f79c85135051b0a46b436ad1e72ab4718f20f1bcd2f7931de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Advanced glycosylation end products</topic><topic>Allosteric properties</topic><topic>Animals</topic><topic>Aptamers</topic><topic>Aptamers, Peptide - 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antagonists & inhibitors</topic><topic>Receptors, Immunologic - chemistry</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Solubility</topic><topic>Spectroscopy</topic><topic>Thioredoxin</topic><topic>Thioredoxins</topic><topic>Thioredoxins - chemistry</topic><topic>Thioredoxins - genetics</topic><topic>Thioredoxins - metabolism</topic><topic>Two-Hybrid System Techniques</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Reverdatto, Sergey</creatorcontrib><creatorcontrib>Rai, Vivek</creatorcontrib><creatorcontrib>Xue, Jing</creatorcontrib><creatorcontrib>Burz, David S</creatorcontrib><creatorcontrib>Schmidt, Ann Marie</creatorcontrib><creatorcontrib>Shekhtman, Alexander</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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We developed a robust method for building a Combinatorial Library of Improved Peptide aptamers (CLIPs) of high complexity, containing ≥3×10(10) independent clones, to be used as a molecular tool in the study of biological pathways. The Thioredoxin scaffold was modified to increase solubility and eliminate aggregation of the peptide aptamers. The CLIPs was used in a yeast two-hybrid screen to identify peptide aptamers that bind to various domains of the Receptor for Advanced Glycation End products (RAGE). NMR spectroscopy was used to identify interaction surfaces between the peptide aptamers and RAGE domains. Cellular functional assays revealed that in addition to directly interfering with known binding sites, peptide aptamer binding distal to ligand sites also inhibits RAGE ligand-induced signal transduction. This finding underscores the potential of using CLIPs to select allosteric inhibitors of biological targets.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23785412</pmid><doi>10.1371/journal.pone.0065180</doi><tpages>e65180</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Advanced glycosylation end products Allosteric properties Animals Aptamers Aptamers, Peptide - chemistry Aptamers, Peptide - pharmacology Binding sites Biochemistry Biology Cell Line Cells (Biology) Cellular signal transduction Chemistry Clips Combinatorial analysis E coli Escherichia coli Glycosylation Ligands Magnetic resonance spectroscopy Male Mammalian cells Medical screening Mice Molecular Docking Simulation Molecular Dynamics Simulation NMR NMR spectroscopy Nuclear magnetic resonance Nuclear magnetic resonance spectroscopy Peptide Library Peptides Protein Binding Protein Conformation Protein Interaction Domains and Motifs Proteins Rats Receptor for Advanced Glycation End Products Receptors, Immunologic - antagonists & inhibitors Receptors, Immunologic - chemistry Signal transduction Signal Transduction - drug effects Solubility Spectroscopy Thioredoxin Thioredoxins Thioredoxins - chemistry Thioredoxins - genetics Thioredoxins - metabolism Two-Hybrid System Techniques Yeast |
| title | Combinatorial library of improved peptide aptamers, CLIPs to inhibit RAGE signal transduction in mammalian cells |
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