Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization
A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and...
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| Veröffentlicht in: | PloS one 2015-08, Vol.10 (8), p.e0134569-e0134569 |
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| creator | Guasch, Alicia Aranguren-Ibáñez, Álvaro Pérez-Luque, Rosa Aparicio, David Martínez-Høyer, Sergio Mulero, M Carmen Serrano-Candelas, Eva Pérez-Riba, Mercè Fita, Ignacio |
| description | A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis-isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans-conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates. |
| doi_str_mv | 10.1371/journal.pone.0134569 |
| format | Article |
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A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis-isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans-conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0134569</identifier><identifier>PMID: 26248042</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Sequence ; Binding Sites ; Biochemistry ; Calcineurin ; Calcineurin - chemistry ; Calcineurin - genetics ; Calcineurin - metabolism ; Calcium ; Calcium-binding protein ; Calmodulin ; Catalysis ; Catalytic Domain ; Chemical properties ; Conserved sequence ; Crystallography, X-Ray ; Cyclophilin A - metabolism ; Cyclosporin A ; Cyclosporine - chemistry ; Cyclosporine - metabolism ; Drug development ; Drug interactions ; Drugs ; Esterases ; Estructura cristal·lina (Sòlids) ; Gene expression ; HEK293 Cells ; Humans ; Interaccions dels medicaments ; Isomerism ; Isomerització ; Isomerization ; Kinases ; Laboratories ; Layer structure (Solids) ; Molecular Dynamics Simulation ; Molecular Sequence Data ; NFATC Transcription Factors - chemistry ; NFATC Transcription Factors - metabolism ; Peptide synthesis ; Peptides ; Phosphatase ; Phosphorylation ; Physiological aspects ; Proline ; Protection and preservation ; Protein Binding ; Protein Isoforms - chemistry ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Proteins ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - isolation & purification ; Regulatory sequences ; Sequence Alignment ; Serine ; Substrates ; Síntesi de pèptids ; Tacrolimus ; Tacrolimus Binding Protein 1A - metabolism ; Threonine ; Transcription factors</subject><ispartof>PloS one, 2015-08, Vol.10 (8), p.e0134569-e0134569</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Guasch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>cc-by (c) Guasch et al., 2015 info:eu-repo/semantics/openAccess <a href="http://creativecommons.org/licenses/by/3.0/es">http://creativecommons.org/licenses/by/3.0/es</a></rights><rights>2015 Guasch et al 2015 Guasch et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c734t-10490be62597cdc8108034cda420d4404735410da6cb76e58489d3f0b0d37d513</citedby><cites>FETCH-LOGICAL-c734t-10490be62597cdc8108034cda420d4404735410da6cb76e58489d3f0b0d37d513</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/PMC4527731/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527731/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,26951,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26248042$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guasch, Alicia</creatorcontrib><creatorcontrib>Aranguren-Ibáñez, Álvaro</creatorcontrib><creatorcontrib>Pérez-Luque, Rosa</creatorcontrib><creatorcontrib>Aparicio, David</creatorcontrib><creatorcontrib>Martínez-Høyer, Sergio</creatorcontrib><creatorcontrib>Mulero, M Carmen</creatorcontrib><creatorcontrib>Serrano-Candelas, Eva</creatorcontrib><creatorcontrib>Pérez-Riba, Mercè</creatorcontrib><creatorcontrib>Fita, Ignacio</creatorcontrib><title>Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis-isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans-conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates.</description><subject>Amino Acid Sequence</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Calcineurin</subject><subject>Calcineurin - chemistry</subject><subject>Calcineurin - genetics</subject><subject>Calcineurin - metabolism</subject><subject>Calcium</subject><subject>Calcium-binding protein</subject><subject>Calmodulin</subject><subject>Catalysis</subject><subject>Catalytic Domain</subject><subject>Chemical properties</subject><subject>Conserved sequence</subject><subject>Crystallography, X-Ray</subject><subject>Cyclophilin A - metabolism</subject><subject>Cyclosporin A</subject><subject>Cyclosporine - chemistry</subject><subject>Cyclosporine - metabolism</subject><subject>Drug development</subject><subject>Drug interactions</subject><subject>Drugs</subject><subject>Esterases</subject><subject>Estructura cristal·lina (Sòlids)</subject><subject>Gene expression</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Interaccions dels medicaments</subject><subject>Isomerism</subject><subject>Isomerització</subject><subject>Isomerization</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Layer structure (Solids)</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Sequence Data</subject><subject>NFATC Transcription Factors - chemistry</subject><subject>NFATC Transcription Factors - metabolism</subject><subject>Peptide synthesis</subject><subject>Peptides</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Proline</subject><subject>Protection and preservation</subject><subject>Protein Binding</subject><subject>Protein Isoforms - chemistry</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Proteins</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - isolation & purification</subject><subject>Regulatory sequences</subject><subject>Sequence Alignment</subject><subject>Serine</subject><subject>Substrates</subject><subject>Síntesi de pèptids</subject><subject>Tacrolimus</subject><subject>Tacrolimus Binding Protein 1A - metabolism</subject><subject>Threonine</subject><subject>Transcription factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>XX2</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYmPwDxBEQkJw0eKv2MkN0lQNqDRpE2O7tRzbaV2cuLOTQvn1OG1WNWgXKIqSOM_7Hp9zfJLkNQRTiBn8tHKdb4Sdrl2jpwBiktHiSXIKC4wmFAH89Oj9JHkRwgqADOeUPk9OEEUkBwSdJnczYaVpdOdNk942SvuF0yEV6cw1lfO1aI2LUdKbX6aVy_Ri435qlW6MSK_1ujVqayfX3tmtTefB1dqbPzvFy-RZJWzQr4bnWXL75eLH7Nvk8urrfHZ-OZEMk3YCASlAqSnKCiaVzCHIASZSCYKAIgQQhjMCgRJUlozqLCd5oXAFSqAwUxnEZ8nbve_ausCHkgQOGUCgADmikZjvCeXEiq-9qYXfcicM3y04v-DCt0ZazSnRqBRQUSQKoqjKM1VWgElEaQlLRaLX5yFaV9ZaSd20XtiR6fhPY5Z84TacZIgx3G8X7g1k6CT3WmovRbsTHj76GwGGeCxKXqCo-TAE9e6-06HltQlSWysa7bp9rjQrCO1zffcP-nhFBmohYtImtjnuVfam_JxgxGIPIIvU9BEqXkrXRsYzV5m4PhJ8HAki0-rf7UJ0IfD5zff_Z6_uxuz7I3aphW2XwdmuP2ZhDJKhuN6F4HV1aAwEvB-Zh2rwfmT4MDJR9ua4qQfRw4zgvzT9D88</recordid><startdate>20150806</startdate><enddate>20150806</enddate><creator>Guasch, Alicia</creator><creator>Aranguren-Ibáñez, Álvaro</creator><creator>Pérez-Luque, Rosa</creator><creator>Aparicio, David</creator><creator>Martínez-Høyer, Sergio</creator><creator>Mulero, M Carmen</creator><creator>Serrano-Candelas, Eva</creator><creator>Pérez-Riba, Mercè</creator><creator>Fita, Ignacio</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>XX2</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150806</creationdate><title>Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization</title><author>Guasch, Alicia ; Aranguren-Ibáñez, Álvaro ; Pérez-Luque, Rosa ; Aparicio, David ; Martínez-Høyer, Sergio ; Mulero, M Carmen ; Serrano-Candelas, Eva ; Pérez-Riba, Mercè ; Fita, Ignacio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c734t-10490be62597cdc8108034cda420d4404735410da6cb76e58489d3f0b0d37d513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amino Acid Sequence</topic><topic>Binding Sites</topic><topic>Biochemistry</topic><topic>Calcineurin</topic><topic>Calcineurin - chemistry</topic><topic>Calcineurin - genetics</topic><topic>Calcineurin - metabolism</topic><topic>Calcium</topic><topic>Calcium-binding protein</topic><topic>Calmodulin</topic><topic>Catalysis</topic><topic>Catalytic Domain</topic><topic>Chemical properties</topic><topic>Conserved sequence</topic><topic>Crystallography, X-Ray</topic><topic>Cyclophilin A - metabolism</topic><topic>Cyclosporin A</topic><topic>Cyclosporine - chemistry</topic><topic>Cyclosporine - metabolism</topic><topic>Drug development</topic><topic>Drug interactions</topic><topic>Drugs</topic><topic>Esterases</topic><topic>Estructura cristal·lina (Sòlids)</topic><topic>Gene expression</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Interaccions dels medicaments</topic><topic>Isomerism</topic><topic>Isomerització</topic><topic>Isomerization</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Layer structure (Solids)</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular Sequence Data</topic><topic>NFATC Transcription Factors - 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A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis-isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans-conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26248042</pmid><doi>10.1371/journal.pone.0134569</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1702090826 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Recercat; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Binding Sites Biochemistry Calcineurin Calcineurin - chemistry Calcineurin - genetics Calcineurin - metabolism Calcium Calcium-binding protein Calmodulin Catalysis Catalytic Domain Chemical properties Conserved sequence Crystallography, X-Ray Cyclophilin A - metabolism Cyclosporin A Cyclosporine - chemistry Cyclosporine - metabolism Drug development Drug interactions Drugs Esterases Estructura cristal·lina (Sòlids) Gene expression HEK293 Cells Humans Interaccions dels medicaments Isomerism Isomerització Isomerization Kinases Laboratories Layer structure (Solids) Molecular Dynamics Simulation Molecular Sequence Data NFATC Transcription Factors - chemistry NFATC Transcription Factors - metabolism Peptide synthesis Peptides Phosphatase Phosphorylation Physiological aspects Proline Protection and preservation Protein Binding Protein Isoforms - chemistry Protein Isoforms - genetics Protein Isoforms - metabolism Proteins Recombinant Proteins - biosynthesis Recombinant Proteins - chemistry Recombinant Proteins - isolation & purification Regulatory sequences Sequence Alignment Serine Substrates Síntesi de pèptids Tacrolimus Tacrolimus Binding Protein 1A - metabolism Threonine Transcription factors |
| title | Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T15%3A14%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Calcineurin%20Undergoes%20a%20Conformational%20Switch%20Evoked%20via%20Peptidyl-Prolyl%20Isomerization&rft.jtitle=PloS%20one&rft.au=Guasch,%20Alicia&rft.date=2015-08-06&rft.volume=10&rft.issue=8&rft.spage=e0134569&rft.epage=e0134569&rft.pages=e0134569-e0134569&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0134569&rft_dat=%3Cgale_plos_%3EA432708017%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1702090826&rft_id=info:pmid/26248042&rft_galeid=A432708017&rft_doaj_id=oai_doaj_org_article_64e2ba1d62a94d6d85dbf07c266b1bd4&rfr_iscdi=true |