Structural Studies of Thyroid Peroxidase Show the Monomer Interacting With Autoantibodies in Thyroid Autoimmune Disease
Abstract Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as destructive (Hashimoto) thyroiditis. Here we report the biophysical and structural characterization of a...
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| Veröffentlicht in: | Endocrinology (Philadelphia) 2020-02, Vol.161 (2), p.1 |
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| creator | Williams, Daniel E Le, Sarah N Hoke, David E Chandler, Peter G Gora, Monika Godlewska, Marlena Banga, J Paul Buckle, Ashley M |
| description | Abstract
Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as destructive (Hashimoto) thyroiditis. Here we report the biophysical and structural characterization of a novel TPO construct containing only the ectodomain of TPO and lacking the propeptide. The construct was enzymatically active and able to bind the patient-derived TR1.9 autoantibody. Analytical ultracentrifugation data suggest that TPO can exist as both a monomer and a dimer. Combined with negative stain electron microscopy and molecular dynamics simulations, these data show that the TR1.9 autoantibody preferentially binds the TPO monomer, revealing conformational changes that bring together previously disparate residues into a continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody complex, this study provides validated TPO constructs that will facilitate further characterization, and advances our understanding of the structural, functional, and antigenic characteristics of TPO, an autoantigen implicated in some of the most common autoimmune diseases. |
| doi_str_mv | 10.1210/endocr/bqaa016 |
| format | Article |
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Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as destructive (Hashimoto) thyroiditis. Here we report the biophysical and structural characterization of a novel TPO construct containing only the ectodomain of TPO and lacking the propeptide. The construct was enzymatically active and able to bind the patient-derived TR1.9 autoantibody. Analytical ultracentrifugation data suggest that TPO can exist as both a monomer and a dimer. Combined with negative stain electron microscopy and molecular dynamics simulations, these data show that the TR1.9 autoantibody preferentially binds the TPO monomer, revealing conformational changes that bring together previously disparate residues into a continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody complex, this study provides validated TPO constructs that will facilitate further characterization, and advances our understanding of the structural, functional, and antigenic characteristics of TPO, an autoantigen implicated in some of the most common autoimmune diseases.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/endocr/bqaa016</identifier><identifier>PMID: 32022847</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Antigenic characteristics ; Antigens ; Autoantibodies ; Autoimmune diseases ; Biosynthesis ; Computer simulation ; Construction ; Development and progression ; Dimers ; Electron microscopy ; Endocrinology ; Epitopes ; Health aspects ; Hormones ; Iodide peroxidase ; Molecular dynamics ; Monomers ; Peroxidase ; Structural analysis ; Structural models ; Structure ; Structure-function relationships ; Thyroid ; Thyroid diseases ; Thyroid gland ; Thyroid hormones ; Thyroiditis ; Thyroiditis, Autoimmune ; Ultracentrifugation</subject><ispartof>Endocrinology (Philadelphia), 2020-02, Vol.161 (2), p.1</ispartof><rights>Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2020</rights><rights>Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><rights>COPYRIGHT 2020 Oxford University Press</rights><rights>Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c464t-9286da649c85d9533af76b2226b3243f358f5bd22f75fa2e8d93bd4abfe926c53</citedby><cites>FETCH-LOGICAL-c464t-9286da649c85d9533af76b2226b3243f358f5bd22f75fa2e8d93bd4abfe926c53</cites><orcidid>0000-0003-2337-6724 ; 0000-0003-2943-9044 ; 0000-0002-8554-663X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32022847$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Williams, Daniel E</creatorcontrib><creatorcontrib>Le, Sarah N</creatorcontrib><creatorcontrib>Hoke, David E</creatorcontrib><creatorcontrib>Chandler, Peter G</creatorcontrib><creatorcontrib>Gora, Monika</creatorcontrib><creatorcontrib>Godlewska, Marlena</creatorcontrib><creatorcontrib>Banga, J Paul</creatorcontrib><creatorcontrib>Buckle, Ashley M</creatorcontrib><title>Structural Studies of Thyroid Peroxidase Show the Monomer Interacting With Autoantibodies in Thyroid Autoimmune Disease</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Abstract
Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as destructive (Hashimoto) thyroiditis. Here we report the biophysical and structural characterization of a novel TPO construct containing only the ectodomain of TPO and lacking the propeptide. The construct was enzymatically active and able to bind the patient-derived TR1.9 autoantibody. Analytical ultracentrifugation data suggest that TPO can exist as both a monomer and a dimer. Combined with negative stain electron microscopy and molecular dynamics simulations, these data show that the TR1.9 autoantibody preferentially binds the TPO monomer, revealing conformational changes that bring together previously disparate residues into a continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody complex, this study provides validated TPO constructs that will facilitate further characterization, and advances our understanding of the structural, functional, and antigenic characteristics of TPO, an autoantigen implicated in some of the most common autoimmune diseases.</description><subject>Antigenic characteristics</subject><subject>Antigens</subject><subject>Autoantibodies</subject><subject>Autoimmune diseases</subject><subject>Biosynthesis</subject><subject>Computer simulation</subject><subject>Construction</subject><subject>Development and progression</subject><subject>Dimers</subject><subject>Electron microscopy</subject><subject>Endocrinology</subject><subject>Epitopes</subject><subject>Health aspects</subject><subject>Hormones</subject><subject>Iodide peroxidase</subject><subject>Molecular dynamics</subject><subject>Monomers</subject><subject>Peroxidase</subject><subject>Structural analysis</subject><subject>Structural models</subject><subject>Structure</subject><subject>Structure-function relationships</subject><subject>Thyroid</subject><subject>Thyroid diseases</subject><subject>Thyroid gland</subject><subject>Thyroid hormones</subject><subject>Thyroiditis</subject><subject>Thyroiditis, Autoimmune</subject><subject>Ultracentrifugation</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqFkc1rFDEYh4Modq1ePUrAix6mnbzJzOwcl9aPQkVhKx5DZvKmmzKTbPNB7X9v1l0rSEFyCEme9-FHfoS8ZvUJA1afotN-DKfDrVI1a5-QBetFU3Wsq5-SRV0zXnUA3RF5EeNNOQoh-HNyxKEGWIpuQe7WKeQx5aAmuk5ZW4zUG3q1uQ_eavoNg_9ptYpI1xt_R9MG6Rfv_IyBXriEQY3Jumv6w6YNXeXklUt28L811j1odi92nrNDem4jFt1L8syoKeKrw35Mvn_8cHX2ubr8-unibHVZjaIVqeph2WrVin5cNrpvOFemawcAaAcOghveLE0zaADTNUYBLnXPBy3UYLCHdmz4MXm3926Dv80Yk5xtHHGalEOfowTeMNED63hB3_6D3vgcXEknQUDTQgcM_lLXakJpnfGpfMJOKlclJ2sZ73euk0eosjTOdvQOjS33jw2MwccY0MhtsLMK95LVcte03DctD02XgTeHtHmYUT_gf6otwPs94PP2f7Jfg2G0Hw</recordid><startdate>20200201</startdate><enddate>20200201</enddate><creator>Williams, Daniel E</creator><creator>Le, Sarah N</creator><creator>Hoke, David E</creator><creator>Chandler, Peter G</creator><creator>Gora, Monika</creator><creator>Godlewska, Marlena</creator><creator>Banga, J Paul</creator><creator>Buckle, Ashley M</creator><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2337-6724</orcidid><orcidid>https://orcid.org/0000-0003-2943-9044</orcidid><orcidid>https://orcid.org/0000-0002-8554-663X</orcidid></search><sort><creationdate>20200201</creationdate><title>Structural Studies of Thyroid Peroxidase Show the Monomer Interacting With Autoantibodies in Thyroid Autoimmune Disease</title><author>Williams, Daniel E ; Le, Sarah N ; Hoke, David E ; Chandler, Peter G ; Gora, Monika ; Godlewska, Marlena ; Banga, J Paul ; Buckle, Ashley M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c464t-9286da649c85d9533af76b2226b3243f358f5bd22f75fa2e8d93bd4abfe926c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antigenic characteristics</topic><topic>Antigens</topic><topic>Autoantibodies</topic><topic>Autoimmune diseases</topic><topic>Biosynthesis</topic><topic>Computer simulation</topic><topic>Construction</topic><topic>Development and progression</topic><topic>Dimers</topic><topic>Electron microscopy</topic><topic>Endocrinology</topic><topic>Epitopes</topic><topic>Health aspects</topic><topic>Hormones</topic><topic>Iodide peroxidase</topic><topic>Molecular dynamics</topic><topic>Monomers</topic><topic>Peroxidase</topic><topic>Structural analysis</topic><topic>Structural models</topic><topic>Structure</topic><topic>Structure-function relationships</topic><topic>Thyroid</topic><topic>Thyroid diseases</topic><topic>Thyroid gland</topic><topic>Thyroid hormones</topic><topic>Thyroiditis</topic><topic>Thyroiditis, Autoimmune</topic><topic>Ultracentrifugation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Williams, Daniel E</creatorcontrib><creatorcontrib>Le, Sarah N</creatorcontrib><creatorcontrib>Hoke, David E</creatorcontrib><creatorcontrib>Chandler, Peter G</creatorcontrib><creatorcontrib>Gora, Monika</creatorcontrib><creatorcontrib>Godlewska, Marlena</creatorcontrib><creatorcontrib>Banga, J Paul</creatorcontrib><creatorcontrib>Buckle, Ashley M</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Williams, Daniel E</au><au>Le, Sarah N</au><au>Hoke, David E</au><au>Chandler, Peter G</au><au>Gora, Monika</au><au>Godlewska, Marlena</au><au>Banga, J Paul</au><au>Buckle, Ashley M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Studies of Thyroid Peroxidase Show the Monomer Interacting With Autoantibodies in Thyroid Autoimmune Disease</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2020-02-01</date><risdate>2020</risdate><volume>161</volume><issue>2</issue><spage>1</spage><pages>1-</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><abstract>Abstract
Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as destructive (Hashimoto) thyroiditis. Here we report the biophysical and structural characterization of a novel TPO construct containing only the ectodomain of TPO and lacking the propeptide. The construct was enzymatically active and able to bind the patient-derived TR1.9 autoantibody. Analytical ultracentrifugation data suggest that TPO can exist as both a monomer and a dimer. Combined with negative stain electron microscopy and molecular dynamics simulations, these data show that the TR1.9 autoantibody preferentially binds the TPO monomer, revealing conformational changes that bring together previously disparate residues into a continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody complex, this study provides validated TPO constructs that will facilitate further characterization, and advances our understanding of the structural, functional, and antigenic characteristics of TPO, an autoantigen implicated in some of the most common autoimmune diseases.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>32022847</pmid><doi>10.1210/endocr/bqaa016</doi><orcidid>https://orcid.org/0000-0003-2337-6724</orcidid><orcidid>https://orcid.org/0000-0003-2943-9044</orcidid><orcidid>https://orcid.org/0000-0002-8554-663X</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Antigenic characteristics Antigens Autoantibodies Autoimmune diseases Biosynthesis Computer simulation Construction Development and progression Dimers Electron microscopy Endocrinology Epitopes Health aspects Hormones Iodide peroxidase Molecular dynamics Monomers Peroxidase Structural analysis Structural models Structure Structure-function relationships Thyroid Thyroid diseases Thyroid gland Thyroid hormones Thyroiditis Thyroiditis, Autoimmune Ultracentrifugation |
| title | Structural Studies of Thyroid Peroxidase Show the Monomer Interacting With Autoantibodies in Thyroid Autoimmune Disease |
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