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Selectional and Mutational Scope of Peptides Sequestering the Jun–Fos Coiled-Coil Domain
The activator protein-1 (AP-1) complex plays a crucial role in numerous pathways, and its ability to induce tumorigenesis is well documented. Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interacti...
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| Published in: | Journal of molecular biology 2008-08, Vol.381 (1), p.73-88 |
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| container_end_page | 88 |
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| container_title | Journal of molecular biology |
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| creator | Hagemann, Urs B. Mason, Jody M. Müller, Kristian M. Arndt, Katja M. |
| description | The activator protein-1 (AP-1) complex plays a crucial role in numerous pathways, and its ability to induce tumorigenesis is well documented. Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interaction to a previously described in vivo protein-fragment complementation assay (PCA). A cJun-based library was screened to enrich for peptides that disrupt the AP-1 complex by binding to the cFos coiled-coil domain. Interestingly, phage display identified one helix, JunWPh1 [phage-selected winning peptide (clone 1) targeting cFos], which differs in only 2 out of 10 randomized positions to JunW (PCA-selected winning peptide targeting cFos). Phage-selected peptides revealed higher affinity to cFos than wild-type cJun, harboring a Tm of 53 °C compared to 16 °C for cFos/cJun or 44 °C for cFos/JunW. In PCA growth assays in the presence of cJun as competitor, phage-selected JunWPh1 conferred shorter generation times than JunW. Bacterial growth was barely detectable, using JunWPh1 as a competitor for the wild-type cJun/cFos interaction, indicating efficient cFos removal from the dimeric wild-type complex. Importantly, all inhibitory peptides were able to interfere with DNA binding as demonstrated in gel shift assays. The selected sequences have consequently improved our ‘bZIP coiled-coil interaction prediction algorithm’ in distinguishing interacting from noninteracting coiled-coil sequences. Predicting and manipulating protein interaction will accelerate the systems biology field, and generated peptides will be valuable tools for analytical and biomedical applications. |
| doi_str_mv | 10.1016/j.jmb.2008.04.030 |
| format | article |
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Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interaction to a previously described in vivo protein-fragment complementation assay (PCA). A cJun-based library was screened to enrich for peptides that disrupt the AP-1 complex by binding to the cFos coiled-coil domain. Interestingly, phage display identified one helix, JunWPh1 [phage-selected winning peptide (clone 1) targeting cFos], which differs in only 2 out of 10 randomized positions to JunW (PCA-selected winning peptide targeting cFos). Phage-selected peptides revealed higher affinity to cFos than wild-type cJun, harboring a Tm of 53 °C compared to 16 °C for cFos/cJun or 44 °C for cFos/JunW. In PCA growth assays in the presence of cJun as competitor, phage-selected JunWPh1 conferred shorter generation times than JunW. Bacterial growth was barely detectable, using JunWPh1 as a competitor for the wild-type cJun/cFos interaction, indicating efficient cFos removal from the dimeric wild-type complex. Importantly, all inhibitory peptides were able to interfere with DNA binding as demonstrated in gel shift assays. The selected sequences have consequently improved our ‘bZIP coiled-coil interaction prediction algorithm’ in distinguishing interacting from noninteracting coiled-coil sequences. 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Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interaction to a previously described in vivo protein-fragment complementation assay (PCA). A cJun-based library was screened to enrich for peptides that disrupt the AP-1 complex by binding to the cFos coiled-coil domain. Interestingly, phage display identified one helix, JunWPh1 [phage-selected winning peptide (clone 1) targeting cFos], which differs in only 2 out of 10 randomized positions to JunW (PCA-selected winning peptide targeting cFos). Phage-selected peptides revealed higher affinity to cFos than wild-type cJun, harboring a Tm of 53 °C compared to 16 °C for cFos/cJun or 44 °C for cFos/JunW. In PCA growth assays in the presence of cJun as competitor, phage-selected JunWPh1 conferred shorter generation times than JunW. Bacterial growth was barely detectable, using JunWPh1 as a competitor for the wild-type cJun/cFos interaction, indicating efficient cFos removal from the dimeric wild-type complex. Importantly, all inhibitory peptides were able to interfere with DNA binding as demonstrated in gel shift assays. The selected sequences have consequently improved our ‘bZIP coiled-coil interaction prediction algorithm’ in distinguishing interacting from noninteracting coiled-coil sequences. Predicting and manipulating protein interaction will accelerate the systems biology field, and generated peptides will be valuable tools for analytical and biomedical applications.</description><subject>Amino Acid Sequence</subject><subject>AP-1</subject><subject>Circular Dichroism</subject><subject>Databases, Protein</subject><subject>DNA - metabolism</subject><subject>Genes, Reporter - genetics</subject><subject>leucine zipper</subject><subject>library selection</subject><subject>Mutation - genetics</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptides</subject><subject>Protein Binding</subject><subject>Protein Denaturation</subject><subject>protein design and engineering</subject><subject>protein stability and specificity</subject><subject>Proto-Oncogene Proteins c-fos - chemistry</subject><subject>Proto-Oncogene Proteins c-fos - genetics</subject><subject>Proto-Oncogene Proteins c-fos - metabolism</subject><subject>Proto-Oncogene Proteins c-jun - chemistry</subject><subject>Proto-Oncogene Proteins c-jun - genetics</subject><subject>Proto-Oncogene Proteins c-jun - metabolism</subject><subject>Thermodynamics</subject><issn>0022-2836</issn><issn>1089-8638</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNqFkc9O3DAQhy1EBQvlAbggn3pLOrYTry1OaPnTViCQtly4WIk9ab1K4iVOKnHjHXjDPkm93ZV6K6fRSN_vp9E3hJwyyBkw-XmVr7o65wAqhyIHAXtkxkDpTEmh9skMgPOMKyEPyVGMKwAoRaEOyCFTpZJ8DjPytMQW7ehDX7W06h29m8Zqty5tWCMNDX3A9egdRrrE5wnjiIPvf9DxJ9JvU__79e06RLoIvkWXbQa9DF3l-4_kQ1O1EU9285g8Xl99X3zJbu9vvi4ubjMrFB-zdDDYprZz0KhqIW3hpHOl05xzV85RsCIhfI512WghmRZYMAVaCq2xASaOyadt73oIf88znY8W27bqMUzRSC14kQLvghw0L1mxAdkWtEOIccDGrAffVcOLYWA25s3KJPNmY95AYZL5lDnblU91h-5fYqc6AedbAJOLXx4HE63H3qLzQ_qAccH_p_4PcIiTbA</recordid><startdate>20080801</startdate><enddate>20080801</enddate><creator>Hagemann, Urs B.</creator><creator>Mason, Jody M.</creator><creator>Müller, Kristian M.</creator><creator>Arndt, Katja M.</creator><general>Elsevier Ltd</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>7QL</scope><scope>7TM</scope><scope>C1K</scope><scope>7X8</scope></search><sort><creationdate>20080801</creationdate><title>Selectional and Mutational Scope of Peptides Sequestering the Jun–Fos Coiled-Coil Domain</title><author>Hagemann, Urs B. ; Mason, Jody M. ; Müller, Kristian M. ; Arndt, Katja M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-1080cfbc709e8b36c4d6dd5d9222d57e31410827eb5f936193e418096399ef013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Amino Acid Sequence</topic><topic>AP-1</topic><topic>Circular Dichroism</topic><topic>Databases, Protein</topic><topic>DNA - metabolism</topic><topic>Genes, Reporter - genetics</topic><topic>leucine zipper</topic><topic>library selection</topic><topic>Mutation - genetics</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptides</topic><topic>Protein Binding</topic><topic>Protein Denaturation</topic><topic>protein design and engineering</topic><topic>protein stability and specificity</topic><topic>Proto-Oncogene Proteins c-fos - chemistry</topic><topic>Proto-Oncogene Proteins c-fos - genetics</topic><topic>Proto-Oncogene Proteins c-fos - metabolism</topic><topic>Proto-Oncogene Proteins c-jun - chemistry</topic><topic>Proto-Oncogene Proteins c-jun - genetics</topic><topic>Proto-Oncogene Proteins c-jun - metabolism</topic><topic>Thermodynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hagemann, Urs B.</creatorcontrib><creatorcontrib>Mason, Jody M.</creatorcontrib><creatorcontrib>Müller, Kristian M.</creatorcontrib><creatorcontrib>Arndt, Katja M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nucleic Acids Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hagemann, Urs B.</au><au>Mason, Jody M.</au><au>Müller, Kristian M.</au><au>Arndt, Katja M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selectional and Mutational Scope of Peptides Sequestering the Jun–Fos Coiled-Coil Domain</atitle><jtitle>Journal of molecular biology</jtitle><addtitle>J Mol Biol</addtitle><date>2008-08-01</date><risdate>2008</risdate><volume>381</volume><issue>1</issue><spage>73</spage><epage>88</epage><pages>73-88</pages><issn>0022-2836</issn><eissn>1089-8638</eissn><abstract>The activator protein-1 (AP-1) complex plays a crucial role in numerous pathways, and its ability to induce tumorigenesis is well documented. Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interaction to a previously described in vivo protein-fragment complementation assay (PCA). A cJun-based library was screened to enrich for peptides that disrupt the AP-1 complex by binding to the cFos coiled-coil domain. Interestingly, phage display identified one helix, JunWPh1 [phage-selected winning peptide (clone 1) targeting cFos], which differs in only 2 out of 10 randomized positions to JunW (PCA-selected winning peptide targeting cFos). Phage-selected peptides revealed higher affinity to cFos than wild-type cJun, harboring a Tm of 53 °C compared to 16 °C for cFos/cJun or 44 °C for cFos/JunW. In PCA growth assays in the presence of cJun as competitor, phage-selected JunWPh1 conferred shorter generation times than JunW. Bacterial growth was barely detectable, using JunWPh1 as a competitor for the wild-type cJun/cFos interaction, indicating efficient cFos removal from the dimeric wild-type complex. Importantly, all inhibitory peptides were able to interfere with DNA binding as demonstrated in gel shift assays. The selected sequences have consequently improved our ‘bZIP coiled-coil interaction prediction algorithm’ in distinguishing interacting from noninteracting coiled-coil sequences. Predicting and manipulating protein interaction will accelerate the systems biology field, and generated peptides will be valuable tools for analytical and biomedical applications.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>18586270</pmid><doi>10.1016/j.jmb.2008.04.030</doi><tpages>16</tpages></addata></record> |
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| subjects | Amino Acid Sequence AP-1 Circular Dichroism Databases, Protein DNA - metabolism Genes, Reporter - genetics leucine zipper library selection Mutation - genetics Peptide Fragments - chemistry Peptide Fragments - metabolism Peptides Protein Binding Protein Denaturation protein design and engineering protein stability and specificity Proto-Oncogene Proteins c-fos - chemistry Proto-Oncogene Proteins c-fos - genetics Proto-Oncogene Proteins c-fos - metabolism Proto-Oncogene Proteins c-jun - chemistry Proto-Oncogene Proteins c-jun - genetics Proto-Oncogene Proteins c-jun - metabolism Thermodynamics |
| title | Selectional and Mutational Scope of Peptides Sequestering the Jun–Fos Coiled-Coil Domain |
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