IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development
A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery...
Gespeichert in:
| Veröffentlicht in: | mAbs 2017-11, Vol.9 (8), p.1231-1252 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1252 |
|---|---|
| container_issue | 8 |
| container_start_page | 1231 |
| container_title | mAbs |
| container_volume | 9 |
| creator | Yang, Danlin Kroe-Barrett, Rachel Singh, Sanjaya Roberts, Christopher J. Laue, Thomas M. |
| description | A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C-region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations. |
| doi_str_mv | 10.1080/19420862.2017.1367074 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_1929897181</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1929897181</sourcerecordid><originalsourceid>FETCH-LOGICAL-c468t-e8b5d6b632526a19332bac48673193073cb454319672e37fea6197a64f6a7bcb3</originalsourceid><addsrcrecordid>eNp9kU1v1DAQhiNERavSn1DkI5cs_khs58KHKigrVeLSnq2J47RGjh1sZ1H-PV52u8AFXzwzft4Za96quiZ4Q7DE70jXUCw53VBMxIYwLrBoXlQX-3qNpcAvTzGn59VVSt_x_oiC41fVOZWS0K5tL6p5-3iLdAiziZDtzuYV1WibUH4y0SBwLqRs4voBbafZWV2Y4BMaQ0Tgs-3DsKJx8fpQBj_8FsJslmz1H2QwO-PCPBmfX1dnI7hkro73ZfXw5fP9zdf67tvt9ubTXa0bLnNtZN8OvOeMtpQD6RijPehGcsFKggXTfdM2JeaCGiZGA5x0AngzchC97tll9f7Qd176yQy6jI7g1BztBHFVAaz698XbJ_UYdqrlsqwYlwZvjw1i-LGYlNVkkzbOgTdhSYp0tJOdIJIUtD2gOoaUohlPYwhWe8PUs2Fqb5g6GlZ0b_7-40n1bE8BPh4A68vKJ_gZohtUhtWFOEbw2ibF_j_jFxMzpzg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1929897181</pqid></control><display><type>article</type><title>IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Yang, Danlin ; Kroe-Barrett, Rachel ; Singh, Sanjaya ; Roberts, Christopher J. ; Laue, Thomas M.</creator><creatorcontrib>Yang, Danlin ; Kroe-Barrett, Rachel ; Singh, Sanjaya ; Roberts, Christopher J. ; Laue, Thomas M.</creatorcontrib><description>A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C-region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations.</description><identifier>ISSN: 1942-0862</identifier><identifier>EISSN: 1942-0870</identifier><identifier>DOI: 10.1080/19420862.2017.1367074</identifier><identifier>PMID: 28812955</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Animals ; antibody discovery ; cooperativity ; Glycosylation ; Humans ; IgG allostery ; IgG subclass selection ; Immunoglobulin Fc Fragments - chemistry ; Immunoglobulin Fc Fragments - immunology ; Immunoglobulin Fc Fragments - metabolism ; Immunoglobulin G - chemistry ; Immunoglobulin G - immunology ; Immunoglobulin G - metabolism ; Immunoglobulin Variable Region - chemistry ; Immunoglobulin Variable Region - immunology ; Immunoglobulin Variable Region - metabolism ; intermolecular interaction ; intramolecular interaction ; Models, Molecular ; molecular engineering ; Protein Binding ; Protein Conformation ; Receptors, IgG - chemistry ; Receptors, IgG - immunology ; Receptors, IgG - metabolism ; Review ; structure and function</subject><ispartof>mAbs, 2017-11, Vol.9 (8), p.1231-1252</ispartof><rights>2017 The Author(s). Published with license by Taylor & Francis Group, LLC © Danlin Yang, Rachel Kroe-Barrett, Sanjaya Singh, Christopher J. Roberts and Thomas M. Laue 2017</rights><rights>2017 The Author(s). Published with license by Taylor & Francis Group, LLC 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c468t-e8b5d6b632526a19332bac48673193073cb454319672e37fea6197a64f6a7bcb3</citedby><cites>FETCH-LOGICAL-c468t-e8b5d6b632526a19332bac48673193073cb454319672e37fea6197a64f6a7bcb3</cites><orcidid>0000-0003-1413-1223 ; 0000-0002-5085-5950</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680800/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680800/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28812955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Danlin</creatorcontrib><creatorcontrib>Kroe-Barrett, Rachel</creatorcontrib><creatorcontrib>Singh, Sanjaya</creatorcontrib><creatorcontrib>Roberts, Christopher J.</creatorcontrib><creatorcontrib>Laue, Thomas M.</creatorcontrib><title>IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development</title><title>mAbs</title><addtitle>MAbs</addtitle><description>A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C-region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations.</description><subject>Animals</subject><subject>antibody discovery</subject><subject>cooperativity</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>IgG allostery</subject><subject>IgG subclass selection</subject><subject>Immunoglobulin Fc Fragments - chemistry</subject><subject>Immunoglobulin Fc Fragments - immunology</subject><subject>Immunoglobulin Fc Fragments - metabolism</subject><subject>Immunoglobulin G - chemistry</subject><subject>Immunoglobulin G - immunology</subject><subject>Immunoglobulin G - metabolism</subject><subject>Immunoglobulin Variable Region - chemistry</subject><subject>Immunoglobulin Variable Region - immunology</subject><subject>Immunoglobulin Variable Region - metabolism</subject><subject>intermolecular interaction</subject><subject>intramolecular interaction</subject><subject>Models, Molecular</subject><subject>molecular engineering</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Receptors, IgG - chemistry</subject><subject>Receptors, IgG - immunology</subject><subject>Receptors, IgG - metabolism</subject><subject>Review</subject><subject>structure and function</subject><issn>1942-0862</issn><issn>1942-0870</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhiNERavSn1DkI5cs_khs58KHKigrVeLSnq2J47RGjh1sZ1H-PV52u8AFXzwzft4Za96quiZ4Q7DE70jXUCw53VBMxIYwLrBoXlQX-3qNpcAvTzGn59VVSt_x_oiC41fVOZWS0K5tL6p5-3iLdAiziZDtzuYV1WibUH4y0SBwLqRs4voBbafZWV2Y4BMaQ0Tgs-3DsKJx8fpQBj_8FsJslmz1H2QwO-PCPBmfX1dnI7hkro73ZfXw5fP9zdf67tvt9ubTXa0bLnNtZN8OvOeMtpQD6RijPehGcsFKggXTfdM2JeaCGiZGA5x0AngzchC97tll9f7Qd176yQy6jI7g1BztBHFVAaz698XbJ_UYdqrlsqwYlwZvjw1i-LGYlNVkkzbOgTdhSYp0tJOdIJIUtD2gOoaUohlPYwhWe8PUs2Fqb5g6GlZ0b_7-40n1bE8BPh4A68vKJ_gZohtUhtWFOEbw2ibF_j_jFxMzpzg</recordid><startdate>20171117</startdate><enddate>20171117</enddate><creator>Yang, Danlin</creator><creator>Kroe-Barrett, Rachel</creator><creator>Singh, Sanjaya</creator><creator>Roberts, Christopher J.</creator><creator>Laue, Thomas M.</creator><general>Taylor & Francis</general><scope>0YH</scope><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><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1413-1223</orcidid><orcidid>https://orcid.org/0000-0002-5085-5950</orcidid></search><sort><creationdate>20171117</creationdate><title>IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development</title><author>Yang, Danlin ; Kroe-Barrett, Rachel ; Singh, Sanjaya ; Roberts, Christopher J. ; Laue, Thomas M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c468t-e8b5d6b632526a19332bac48673193073cb454319672e37fea6197a64f6a7bcb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>antibody discovery</topic><topic>cooperativity</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>IgG allostery</topic><topic>IgG subclass selection</topic><topic>Immunoglobulin Fc Fragments - chemistry</topic><topic>Immunoglobulin Fc Fragments - immunology</topic><topic>Immunoglobulin Fc Fragments - metabolism</topic><topic>Immunoglobulin G - chemistry</topic><topic>Immunoglobulin G - immunology</topic><topic>Immunoglobulin G - metabolism</topic><topic>Immunoglobulin Variable Region - chemistry</topic><topic>Immunoglobulin Variable Region - immunology</topic><topic>Immunoglobulin Variable Region - metabolism</topic><topic>intermolecular interaction</topic><topic>intramolecular interaction</topic><topic>Models, Molecular</topic><topic>molecular engineering</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Receptors, IgG - chemistry</topic><topic>Receptors, IgG - immunology</topic><topic>Receptors, IgG - metabolism</topic><topic>Review</topic><topic>structure and function</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Danlin</creatorcontrib><creatorcontrib>Kroe-Barrett, Rachel</creatorcontrib><creatorcontrib>Singh, Sanjaya</creatorcontrib><creatorcontrib>Roberts, Christopher J.</creatorcontrib><creatorcontrib>Laue, Thomas M.</creatorcontrib><collection>Taylor & Francis Open Access</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>mAbs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Danlin</au><au>Kroe-Barrett, Rachel</au><au>Singh, Sanjaya</au><au>Roberts, Christopher J.</au><au>Laue, Thomas M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development</atitle><jtitle>mAbs</jtitle><addtitle>MAbs</addtitle><date>2017-11-17</date><risdate>2017</risdate><volume>9</volume><issue>8</issue><spage>1231</spage><epage>1252</epage><pages>1231-1252</pages><issn>1942-0862</issn><eissn>1942-0870</eissn><abstract>A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C-region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>28812955</pmid><doi>10.1080/19420862.2017.1367074</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0003-1413-1223</orcidid><orcidid>https://orcid.org/0000-0002-5085-5950</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1942-0862 |
| ispartof | mAbs, 2017-11, Vol.9 (8), p.1231-1252 |
| issn | 1942-0862 1942-0870 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1929897181 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals antibody discovery cooperativity Glycosylation Humans IgG allostery IgG subclass selection Immunoglobulin Fc Fragments - chemistry Immunoglobulin Fc Fragments - immunology Immunoglobulin Fc Fragments - metabolism Immunoglobulin G - chemistry Immunoglobulin G - immunology Immunoglobulin G - metabolism Immunoglobulin Variable Region - chemistry Immunoglobulin Variable Region - immunology Immunoglobulin Variable Region - metabolism intermolecular interaction intramolecular interaction Models, Molecular molecular engineering Protein Binding Protein Conformation Receptors, IgG - chemistry Receptors, IgG - immunology Receptors, IgG - metabolism Review structure and function |
| title | IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T00%3A18%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=IgG%20cooperativity%20-%20Is%20there%20allostery?%20Implications%20for%20antibody%20functions%20and%20therapeutic%20antibody%20development&rft.jtitle=mAbs&rft.au=Yang,%20Danlin&rft.date=2017-11-17&rft.volume=9&rft.issue=8&rft.spage=1231&rft.epage=1252&rft.pages=1231-1252&rft.issn=1942-0862&rft.eissn=1942-0870&rft_id=info:doi/10.1080/19420862.2017.1367074&rft_dat=%3Cproquest_pubme%3E1929897181%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1929897181&rft_id=info:pmid/28812955&rfr_iscdi=true |