Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity
Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the m...
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| creator | Le, Sarah N Porebski, Benjamin T McCoey, Julia Fodor, James Riley, Blake Godlewska, Marlena Góra, Monika Czarnocka, Barbara Banga, J Paul Hoke, David E Kass, Itamar Buckle, Ashley M |
| description | Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data. |
| doi_str_mv | 10.1371/journal.pone.0142615 |
| format | Article |
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Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0142615</identifier><identifier>PMID: 26623656</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Sequence ; Antigenic determinants ; Antigens ; Autoantibodies ; Autoantigens - chemistry ; Autoantigens - immunology ; Autoantigens - metabolism ; Biochemistry ; Biosynthesis ; C-Terminus ; Care and treatment ; Cell Membrane - enzymology ; Coalescing ; Crystal structure ; Cytotoxicity ; Dimerization ; Dissociation ; Endocrinology ; Enzyme Stability ; Epidermal growth factor ; Epitope mapping ; Extracellular Space - enzymology ; Health education ; Hormones ; Humans ; Immunoglobulins ; Iodide peroxidase ; Iodide Peroxidase - chemistry ; Iodide Peroxidase - immunology ; Iodide Peroxidase - metabolism ; Iron-Binding Proteins - chemistry ; Iron-Binding Proteins - immunology ; Iron-Binding Proteins - metabolism ; Mapping ; Modelling ; Molecular biology ; Molecular Dynamics Simulation ; Molecular modelling ; Molecular Sequence Data ; Molecular structure ; Monomers ; Mutagenesis ; Peroxidase ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Proteins ; Risk factors ; Steric hindrance ; Thermodynamics ; Thyroid ; Thyroid diseases ; Thyroid hormones ; Thyroxine</subject><ispartof>PloS one, 2015-12, Vol.10 (12), p.e0142615-e0142615</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Le 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 Le et al 2015 Le et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c762t-d9a2b1fd61f3f60d9bfbaf359e62b433ab1487644879a07d5ac139db5cf568703</citedby><cites>FETCH-LOGICAL-c762t-d9a2b1fd61f3f60d9bfbaf359e62b433ab1487644879a07d5ac139db5cf568703</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/PMC4666655/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666655/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26623656$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Permyakov, Eugene A.</contributor><creatorcontrib>Le, Sarah N</creatorcontrib><creatorcontrib>Porebski, Benjamin T</creatorcontrib><creatorcontrib>McCoey, Julia</creatorcontrib><creatorcontrib>Fodor, James</creatorcontrib><creatorcontrib>Riley, Blake</creatorcontrib><creatorcontrib>Godlewska, Marlena</creatorcontrib><creatorcontrib>Góra, Monika</creatorcontrib><creatorcontrib>Czarnocka, Barbara</creatorcontrib><creatorcontrib>Banga, J Paul</creatorcontrib><creatorcontrib>Hoke, David E</creatorcontrib><creatorcontrib>Kass, Itamar</creatorcontrib><creatorcontrib>Buckle, Ashley M</creatorcontrib><title>Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data.</description><subject>Amino Acid Sequence</subject><subject>Antigenic determinants</subject><subject>Antigens</subject><subject>Autoantibodies</subject><subject>Autoantigens - chemistry</subject><subject>Autoantigens - immunology</subject><subject>Autoantigens - metabolism</subject><subject>Biochemistry</subject><subject>Biosynthesis</subject><subject>C-Terminus</subject><subject>Care and treatment</subject><subject>Cell Membrane - enzymology</subject><subject>Coalescing</subject><subject>Crystal structure</subject><subject>Cytotoxicity</subject><subject>Dimerization</subject><subject>Dissociation</subject><subject>Endocrinology</subject><subject>Enzyme Stability</subject><subject>Epidermal growth factor</subject><subject>Epitope mapping</subject><subject>Extracellular Space - enzymology</subject><subject>Health education</subject><subject>Hormones</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Iodide peroxidase</subject><subject>Iodide Peroxidase - chemistry</subject><subject>Iodide Peroxidase - immunology</subject><subject>Iodide Peroxidase - metabolism</subject><subject>Iron-Binding Proteins - chemistry</subject><subject>Iron-Binding Proteins - immunology</subject><subject>Iron-Binding Proteins - metabolism</subject><subject>Mapping</subject><subject>Modelling</subject><subject>Molecular biology</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular modelling</subject><subject>Molecular Sequence Data</subject><subject>Molecular structure</subject><subject>Monomers</subject><subject>Mutagenesis</subject><subject>Peroxidase</subject><subject>Protein Multimerization</subject><subject>Protein Structure, Quaternary</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Risk factors</subject><subject>Steric hindrance</subject><subject>Thermodynamics</subject><subject>Thyroid</subject><subject>Thyroid diseases</subject><subject>Thyroid 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Blake</au><au>Godlewska, Marlena</au><au>Góra, Monika</au><au>Czarnocka, Barbara</au><au>Banga, J Paul</au><au>Hoke, David E</au><au>Kass, Itamar</au><au>Buckle, Ashley M</au><au>Permyakov, Eugene A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-12-01</date><risdate>2015</risdate><volume>10</volume><issue>12</issue><spage>e0142615</spage><epage>e0142615</epage><pages>e0142615-e0142615</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26623656</pmid><doi>10.1371/journal.pone.0142615</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-12, Vol.10 (12), p.e0142615-e0142615 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1738477718 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Antigenic determinants Antigens Autoantibodies Autoantigens - chemistry Autoantigens - immunology Autoantigens - metabolism Biochemistry Biosynthesis C-Terminus Care and treatment Cell Membrane - enzymology Coalescing Crystal structure Cytotoxicity Dimerization Dissociation Endocrinology Enzyme Stability Epidermal growth factor Epitope mapping Extracellular Space - enzymology Health education Hormones Humans Immunoglobulins Iodide peroxidase Iodide Peroxidase - chemistry Iodide Peroxidase - immunology Iodide Peroxidase - metabolism Iron-Binding Proteins - chemistry Iron-Binding Proteins - immunology Iron-Binding Proteins - metabolism Mapping Modelling Molecular biology Molecular Dynamics Simulation Molecular modelling Molecular Sequence Data Molecular structure Monomers Mutagenesis Peroxidase Protein Multimerization Protein Structure, Quaternary Protein Structure, Tertiary Proteins Risk factors Steric hindrance Thermodynamics Thyroid Thyroid diseases Thyroid hormones Thyroxine |
| title | Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity |
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