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CD44 Binding to Hyaluronic Acid Is Redox Regulated by a Labile Disulfide Bond in the Hyaluronic Acid Binding Site
CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity....
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Published in: | PloS one 2015-09, Vol.10 (9), p.e0138137-e0138137 |
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description | CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity. We have identified one such disulfide bond in CD44 formed by Cys77 and Cys97 that stabilises the HA binding groove. This bond is labile on the surface of leukocytes treated with chemical and enzymatic reducing agents. Analysis of CD44 crystal structures reveal the disulfide bond to be solvent accessible and in the-LH hook configuration characteristic of labile disulfide bonds. Kinetic trapping and binding experiments on CD44-Fc chimeric proteins show the bond is preferentially reduced over the other disulfide bonds in CD44 and reduction inhibits the CD44-HA interaction. Furthermore cells transfected with CD44 no longer adhere to HA coated surfaces after pre-treatment with reducing agents. The implications of CD44 redox regulation are discussed in the context of immune function, disease and therapeutic strategies. |
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Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity. We have identified one such disulfide bond in CD44 formed by Cys77 and Cys97 that stabilises the HA binding groove. This bond is labile on the surface of leukocytes treated with chemical and enzymatic reducing agents. Analysis of CD44 crystal structures reveal the disulfide bond to be solvent accessible and in the-LH hook configuration characteristic of labile disulfide bonds. Kinetic trapping and binding experiments on CD44-Fc chimeric proteins show the bond is preferentially reduced over the other disulfide bonds in CD44 and reduction inhibits the CD44-HA interaction. Furthermore cells transfected with CD44 no longer adhere to HA coated surfaces after pre-treatment with reducing agents. The implications of CD44 redox regulation are discussed in the context of immune function, disease and therapeutic strategies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0138137</identifier><identifier>PMID: 26379032</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Allosteric properties ; Animals ; Binding Sites ; Blood clots ; Blood platelets ; Bonds (Securities) ; Cancer ; CD44 antigen ; Cell Adhesion ; Cell Line ; Cell surface ; Chemical bonds ; Chemical properties ; CHO Cells ; Cricetulus ; Crystal structure ; Crystallography, X-Ray ; Dendritic cells ; Disulfide bonds ; Enzymes ; Extracellular matrix ; Fc receptors ; Humans ; Hyaluronan Receptors - genetics ; Hyaluronan Receptors - metabolism ; Hyaluronan Receptors - ultrastructure ; Hyaluronic acid ; Hyaluronic Acid - metabolism ; Hydrothermal crystal growth ; Immune response ; Leukocytes ; Lymphocytes ; Mass spectrometry ; Mice ; Oxidation-Reduction ; Pathology ; Protein Binding ; Proteins ; Receptors, Fc - genetics ; Receptors, Fc - metabolism ; Recombinant Fusion Proteins - metabolism ; Reducing agents ; Rheumatoid arthritis ; Scientific imaging ; T cell receptors ; Transfection</subject><ispartof>PloS one, 2015-09, Vol.10 (9), p.e0138137-e0138137</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Kellett-Clarke 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>2015 Kellett-Clarke et al 2015 Kellett-Clarke et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-d7aa486ba72e639541d6c7a1fe7463826d9af66fcc62d7e83731ae958e05cfb23</citedby><cites>FETCH-LOGICAL-c758t-d7aa486ba72e639541d6c7a1fe7463826d9af66fcc62d7e83731ae958e05cfb23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1719287194/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1719287194?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26379032$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Yodoi, Junji</contributor><creatorcontrib>Kellett-Clarke, Helena</creatorcontrib><creatorcontrib>Stegmann, Monika</creatorcontrib><creatorcontrib>Barclay, A Neil</creatorcontrib><creatorcontrib>Metcalfe, Clive</creatorcontrib><title>CD44 Binding to Hyaluronic Acid Is Redox Regulated by a Labile Disulfide Bond in the Hyaluronic Acid Binding Site</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity. We have identified one such disulfide bond in CD44 formed by Cys77 and Cys97 that stabilises the HA binding groove. This bond is labile on the surface of leukocytes treated with chemical and enzymatic reducing agents. Analysis of CD44 crystal structures reveal the disulfide bond to be solvent accessible and in the-LH hook configuration characteristic of labile disulfide bonds. Kinetic trapping and binding experiments on CD44-Fc chimeric proteins show the bond is preferentially reduced over the other disulfide bonds in CD44 and reduction inhibits the CD44-HA interaction. Furthermore cells transfected with CD44 no longer adhere to HA coated surfaces after pre-treatment with reducing agents. The implications of CD44 redox regulation are discussed in the context of immune function, disease and therapeutic strategies.</description><subject>Acids</subject><subject>Allosteric properties</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Blood clots</subject><subject>Blood platelets</subject><subject>Bonds (Securities)</subject><subject>Cancer</subject><subject>CD44 antigen</subject><subject>Cell Adhesion</subject><subject>Cell Line</subject><subject>Cell surface</subject><subject>Chemical bonds</subject><subject>Chemical properties</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Dendritic cells</subject><subject>Disulfide bonds</subject><subject>Enzymes</subject><subject>Extracellular matrix</subject><subject>Fc receptors</subject><subject>Humans</subject><subject>Hyaluronan Receptors - genetics</subject><subject>Hyaluronan Receptors - metabolism</subject><subject>Hyaluronan Receptors - ultrastructure</subject><subject>Hyaluronic acid</subject><subject>Hyaluronic Acid - metabolism</subject><subject>Hydrothermal crystal growth</subject><subject>Immune response</subject><subject>Leukocytes</subject><subject>Lymphocytes</subject><subject>Mass spectrometry</subject><subject>Mice</subject><subject>Oxidation-Reduction</subject><subject>Pathology</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Receptors, Fc - genetics</subject><subject>Receptors, Fc - metabolism</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Reducing agents</subject><subject>Rheumatoid arthritis</subject><subject>Scientific imaging</subject><subject>T cell receptors</subject><subject>Transfection</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk99v0zAQxyMEYmPwHyCwhITgoSX-7bxM6jpglSpN2oBXy7Wd1pVrd3GC1v-eZE2nBvaALJ2t8-e-Z599WfYW5mOIOfyyjk0VlB9vY7DjHGLRep9lp7DAaMRQjp8frU-yVymt85xiwdjL7AQxzIsco9PsbnpJCLhwwbiwBHUEVzvlmyoGp8FEOwNmCdxYE-9bu2y8qq0Bix1QYK4Wzltw6VLjS2csuIjBABdAvbL_iBz0b11tX2cvSuWTfdPPZ9nPb19_TK9G8-vvs-lkPtKcinpkuFJEsIXiyDJcUAIN01zB0nLCsEDMFKpkrNSaIcOtwBxDZQsqbE51uUD4LHu_1936mGRfrSQhhwUSrSEtMdsTJqq13FZuo6qdjMrJB0esllJVtdPeSs2KvDAIQlIiYnIhKM1twYzmmIsS0VbrvM_WLDbWaBvqSvmB6HAnuJVcxt-SUE4K2gl86gWqeNfYVMuNS9p6r4KNzcO5cUEoIR364S_06dv11FK1F3ChjG1e3YnKCUGioFywrkrjJ6h2GLtxuv1aZfvKw4DPg4CWqe19vVRNSnJ2e_P_7PWvIfvxiF1Z5etVir6pXQxpCJI9qKuYUmXLxyLDXHadcaiG7DpD9p3Rhr07fqDHoEMr4D-nqQZX</recordid><startdate>20150917</startdate><enddate>20150917</enddate><creator>Kellett-Clarke, Helena</creator><creator>Stegmann, Monika</creator><creator>Barclay, A Neil</creator><creator>Metcalfe, Clive</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>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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150917</creationdate><title>CD44 Binding to Hyaluronic Acid Is Redox Regulated by a Labile Disulfide Bond in the Hyaluronic Acid Binding Site</title><author>Kellett-Clarke, Helena ; Stegmann, Monika ; Barclay, A Neil ; Metcalfe, Clive</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-d7aa486ba72e639541d6c7a1fe7463826d9af66fcc62d7e83731ae958e05cfb23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acids</topic><topic>Allosteric properties</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Blood clots</topic><topic>Blood platelets</topic><topic>Bonds (Securities)</topic><topic>Cancer</topic><topic>CD44 antigen</topic><topic>Cell Adhesion</topic><topic>Cell Line</topic><topic>Cell surface</topic><topic>Chemical bonds</topic><topic>Chemical properties</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>Dendritic cells</topic><topic>Disulfide bonds</topic><topic>Enzymes</topic><topic>Extracellular matrix</topic><topic>Fc receptors</topic><topic>Humans</topic><topic>Hyaluronan Receptors - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kellett-Clarke, Helena</au><au>Stegmann, Monika</au><au>Barclay, A Neil</au><au>Metcalfe, Clive</au><au>Yodoi, Junji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD44 Binding to Hyaluronic Acid Is Redox Regulated by a Labile Disulfide Bond in the Hyaluronic Acid Binding Site</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-09-17</date><risdate>2015</risdate><volume>10</volume><issue>9</issue><spage>e0138137</spage><epage>e0138137</epage><pages>e0138137-e0138137</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity. We have identified one such disulfide bond in CD44 formed by Cys77 and Cys97 that stabilises the HA binding groove. This bond is labile on the surface of leukocytes treated with chemical and enzymatic reducing agents. Analysis of CD44 crystal structures reveal the disulfide bond to be solvent accessible and in the-LH hook configuration characteristic of labile disulfide bonds. Kinetic trapping and binding experiments on CD44-Fc chimeric proteins show the bond is preferentially reduced over the other disulfide bonds in CD44 and reduction inhibits the CD44-HA interaction. Furthermore cells transfected with CD44 no longer adhere to HA coated surfaces after pre-treatment with reducing agents. The implications of CD44 redox regulation are discussed in the context of immune function, disease and therapeutic strategies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26379032</pmid><doi>10.1371/journal.pone.0138137</doi><tpages>e0138137</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acids Allosteric properties Animals Binding Sites Blood clots Blood platelets Bonds (Securities) Cancer CD44 antigen Cell Adhesion Cell Line Cell surface Chemical bonds Chemical properties CHO Cells Cricetulus Crystal structure Crystallography, X-Ray Dendritic cells Disulfide bonds Enzymes Extracellular matrix Fc receptors Humans Hyaluronan Receptors - genetics Hyaluronan Receptors - metabolism Hyaluronan Receptors - ultrastructure Hyaluronic acid Hyaluronic Acid - metabolism Hydrothermal crystal growth Immune response Leukocytes Lymphocytes Mass spectrometry Mice Oxidation-Reduction Pathology Protein Binding Proteins Receptors, Fc - genetics Receptors, Fc - metabolism Recombinant Fusion Proteins - metabolism Reducing agents Rheumatoid arthritis Scientific imaging T cell receptors Transfection |
title | CD44 Binding to Hyaluronic Acid Is Redox Regulated by a Labile Disulfide Bond in the Hyaluronic Acid Binding Site |
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