Adiponectin Multimerization Is Dependent on Conserved Lysines in the Collagenous Domain: Evidence for Regulation of Multimerization by Alterations in Posttranslational Modifications
Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer compositi...
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| Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 2006-07, Vol.20 (7), p.1673-1687 |
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| container_title | Molecular endocrinology (Baltimore, Md.) |
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| creator | Richards, Ayanthi A Stephens, Tim Charlton, Hayley K Jones, Alun Macdonald, Graeme A Prins, Johannes B Whitehead, Jonathan P |
| description | Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2′-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors. |
| doi_str_mv | 10.1210/me.2005-0390 |
| format | Article |
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Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2′-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/me.2005-0390</identifier><identifier>PMID: 16497731</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>2,2'-Dipyridyl - pharmacology ; Adiponectin - chemistry ; Adiponectin - metabolism ; Amino Acid Sequence ; Animals ; Bacteria - genetics ; Bacteria - metabolism ; CHO Cells ; Collagen - metabolism ; Conserved Sequence ; Cricetinae ; Dimerization ; Gene Expression ; Glucose - pharmacology ; Glycosylation ; Humans ; Hydroxylation - drug effects ; Lysine - metabolism ; Mass Spectrometry ; Models, Biological ; Molecular Sequence Data ; Multiprotein Complexes - metabolism ; Proline - metabolism ; Protein Isoforms - metabolism ; Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Recombinant Proteins - chemistry</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2006-07, Vol.20 (7), p.1673-1687</ispartof><rights>Copyright © 2006 by The Endocrine Society 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-53ffe62656e2a492b6c1273f8f7fd2b3366aba66b0b1f4ec02a88b20d9e3bb23</citedby><cites>FETCH-LOGICAL-c431t-53ffe62656e2a492b6c1273f8f7fd2b3366aba66b0b1f4ec02a88b20d9e3bb23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16497731$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Richards, Ayanthi A</creatorcontrib><creatorcontrib>Stephens, Tim</creatorcontrib><creatorcontrib>Charlton, Hayley K</creatorcontrib><creatorcontrib>Jones, Alun</creatorcontrib><creatorcontrib>Macdonald, Graeme A</creatorcontrib><creatorcontrib>Prins, Johannes B</creatorcontrib><creatorcontrib>Whitehead, Jonathan P</creatorcontrib><title>Adiponectin Multimerization Is Dependent on Conserved Lysines in the Collagenous Domain: Evidence for Regulation of Multimerization by Alterations in Posttranslational Modifications</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2′-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors.</description><subject>2,2'-Dipyridyl - pharmacology</subject><subject>Adiponectin - chemistry</subject><subject>Adiponectin - metabolism</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Bacteria - genetics</subject><subject>Bacteria - metabolism</subject><subject>CHO Cells</subject><subject>Collagen - metabolism</subject><subject>Conserved Sequence</subject><subject>Cricetinae</subject><subject>Dimerization</subject><subject>Gene Expression</subject><subject>Glucose - pharmacology</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Hydroxylation - drug effects</subject><subject>Lysine - metabolism</subject><subject>Mass Spectrometry</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Proline - metabolism</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Processing, Post-Translational</subject><subject>Protein Structure, Tertiary</subject><subject>Recombinant Proteins - chemistry</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtv1DAUhS0EokNhxxp5BRtS_Egch91oKFBpKhDq3rKT6-IqsYPtVBr-F_8PTzMSC2BlXfk75z4OQi8puaCMkncTXDBCmorwjjxCG9rVddV1tH2MNkRKWUlJujP0LKU7QmjdSPoUnVFRd23L6Qb92g5uDh767Dy-XsbsJojup84ueHyV8AeYwQ_gMy71LvgE8R4GvD8k5yHhIsrfoXyMo74FH5aiCJN2_j2-vHdF1wO2IeJvcLuMq2mwf_UxB7wdM8SH6sH0a0g5R-3TKtIjvg6Ds65fkefoidVjghen9xzdfLy82X2u9l8-Xe22-6qvOc1Vw60FwUQjgOm6Y0b0lLXcStvagRnOhdBGC2GIobaGnjAtpWFk6IAbw_g5er3azjH8WCBlNbnUQ9nVQ1lVCdmU49ZtAd-uYB9DShGsmqObdDwoStQxJTWBOqakjikV_NXJdzETDH_gUywFeLMCYZn_Z1WdrPhKlpRCH0soc4SU1F1YYjlb-vcAvwFUIq_-</recordid><startdate>20060701</startdate><enddate>20060701</enddate><creator>Richards, Ayanthi A</creator><creator>Stephens, Tim</creator><creator>Charlton, Hayley K</creator><creator>Jones, Alun</creator><creator>Macdonald, Graeme A</creator><creator>Prins, Johannes B</creator><creator>Whitehead, Jonathan P</creator><general>Endocrine Society</general><general>Oxford University Press</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>7X8</scope></search><sort><creationdate>20060701</creationdate><title>Adiponectin Multimerization Is Dependent on Conserved Lysines in the Collagenous Domain: Evidence for Regulation of Multimerization by Alterations in Posttranslational Modifications</title><author>Richards, Ayanthi A ; Stephens, Tim ; Charlton, Hayley K ; Jones, Alun ; Macdonald, Graeme A ; Prins, Johannes B ; Whitehead, Jonathan P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c431t-53ffe62656e2a492b6c1273f8f7fd2b3366aba66b0b1f4ec02a88b20d9e3bb23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>2,2'-Dipyridyl - pharmacology</topic><topic>Adiponectin - chemistry</topic><topic>Adiponectin - metabolism</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Bacteria - genetics</topic><topic>Bacteria - metabolism</topic><topic>CHO Cells</topic><topic>Collagen - metabolism</topic><topic>Conserved Sequence</topic><topic>Cricetinae</topic><topic>Dimerization</topic><topic>Gene Expression</topic><topic>Glucose - pharmacology</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>Hydroxylation - drug effects</topic><topic>Lysine - metabolism</topic><topic>Mass Spectrometry</topic><topic>Models, Biological</topic><topic>Molecular Sequence Data</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Proline - metabolism</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein Processing, Post-Translational</topic><topic>Protein Structure, Tertiary</topic><topic>Recombinant Proteins - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Richards, Ayanthi A</creatorcontrib><creatorcontrib>Stephens, Tim</creatorcontrib><creatorcontrib>Charlton, Hayley K</creatorcontrib><creatorcontrib>Jones, Alun</creatorcontrib><creatorcontrib>Macdonald, Graeme A</creatorcontrib><creatorcontrib>Prins, Johannes B</creatorcontrib><creatorcontrib>Whitehead, Jonathan P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Richards, Ayanthi A</au><au>Stephens, Tim</au><au>Charlton, Hayley K</au><au>Jones, Alun</au><au>Macdonald, Graeme A</au><au>Prins, Johannes B</au><au>Whitehead, Jonathan P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adiponectin Multimerization Is Dependent on Conserved Lysines in the Collagenous Domain: Evidence for Regulation of Multimerization by Alterations in Posttranslational Modifications</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2006-07-01</date><risdate>2006</risdate><volume>20</volume><issue>7</issue><spage>1673</spage><epage>1687</epage><pages>1673-1687</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2′-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>16497731</pmid><doi>10.1210/me.2005-0390</doi><tpages>15</tpages></addata></record> |
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| ispartof | Molecular endocrinology (Baltimore, Md.), 2006-07, Vol.20 (7), p.1673-1687 |
| issn | 0888-8809 1944-9917 |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | 2,2'-Dipyridyl - pharmacology Adiponectin - chemistry Adiponectin - metabolism Amino Acid Sequence Animals Bacteria - genetics Bacteria - metabolism CHO Cells Collagen - metabolism Conserved Sequence Cricetinae Dimerization Gene Expression Glucose - pharmacology Glycosylation Humans Hydroxylation - drug effects Lysine - metabolism Mass Spectrometry Models, Biological Molecular Sequence Data Multiprotein Complexes - metabolism Proline - metabolism Protein Isoforms - metabolism Protein Processing, Post-Translational Protein Structure, Tertiary Recombinant Proteins - chemistry |
| title | Adiponectin Multimerization Is Dependent on Conserved Lysines in the Collagenous Domain: Evidence for Regulation of Multimerization by Alterations in Posttranslational Modifications |
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