Crystal structure of the TSH receptor bound to a blocking type TSHR autoantibody

Sanders, Paul G.; Young, Stuart; Sanders, Jane; Kabelis, Katarzyna; Baker, Stuart; Sullivan, Andrew; Evans, Michele K.; Clark, J. C. D.; Wilmot, Jane; Hu, Xiaoling; Roberts, Emma; Powell, Michael J.; Miguel, Ricardo Núñez; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1530/jme-10-0127

Cited by 98 publications

(167 citation statements)

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“…Importantly, human monoclonal TSAbs from patients with Graves' disease have also been derived, providing detail into their molecular and biochemical properties, and pathogenicity in vivo (11)(12)(13). A major advance has been the delineation of the atomic structures of immune complex of human monoclonal TSAb, M22 and human monoclonal TSBAb, and K1-70 with human TSHR A-subunit (14)(15)(16). The structures reveal the epitopes for M22 and K1-70 to be dependent on discontinuous determinants on leucine-rich repeat (LRR) regions of TSHR A-subunit (14,15).…”

mentioning

confidence: 99%

“…A major advance has been the delineation of the atomic structures of immune complex of human monoclonal TSAb, M22 and human monoclonal TSBAb, and K1-70 with human TSHR A-subunit (14)(15)(16). The structures reveal the epitopes for M22 and K1-70 to be dependent on discontinuous determinants on leucine-rich repeat (LRR) regions of TSHR A-subunit (14,15). Importantly, TSHR residues R38, K58, R80, H105, and K129 were critical for recognition of the receptor by M22 (14).…”

mentioning

confidence: 99%

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Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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Graves’ disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves’ disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves’ disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.

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confidence: 99%

mentioning

confidence: 99%

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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“…65 Å resolution; Sanders et al 2004) and a thyroid-blocking human MAb K1-70 (2 . 22 Å resolution; Sanders et al 2011) have been described. In addition, a mouse TSHR MAb (RSR-B2) with potent TSH-binding inhibiting and TSHR antagonist activities has also been crystallised (3 .…”

Section: Introductionmentioning

confidence: 99%

“…55 Å ; Sanders et al 2007a) and with K1-70 (1 . 9 Å ; Sanders et al 2011) provided molecular details of the interactions of M22 and K1-70 with the receptor. To study the interactions of TSH with the TSHR, a comparative model of a TSH-TSHR LRD complex has been produced using the crystal structures of M22-TSHR LRD (Sanders et al 2007a) and FSH-FSH receptor (FSHR;Fan & Hendrickson 2005) complexes to model the binding arrangements between TSH and the TSHR (Nú ñez Miguel et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor

Miguel

Sanders

et al. 2012

Journal of Molecular Endocrinology

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Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1-18 to the TSH receptor (TSHR) leucinerich domain (LRD) was predicted using charge-charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1-70. The interactions of K1-18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22-TSHR LRD and K1-70-TSHR LRD complexes. Furthermore, the predicted position of K1-18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1-18. A similar approach was adopted for predicting binding of a mouse thyroid-blocking MAb RSR-B2 to the TSHR. K1-18 is predicted to bind to the TSHR LRD in a similar way as TSH and M22. The binding analysis suggests that K1-18 light chain (LC) mimics binding of the TSH-a chain and the heavy chain (HC) mimics binding of the TSH-b chain. By contrast, M22 HC mimics the interactions of TSH-a while M22 LC mimics TSH-b in interactions with the TSHR. The observed interactions in the M22-TSHR LRD and K1-70-TSHR LRD complexes (crystal structures) with TSH-TSHR LRD (comparative model) and K1-18-TSHR LRD (predictive binding) suggest that K1-18 and M22 interactions with the receptor may reflect interaction of thyroid-stimulating autoantibodies in general. Furthermore, K1-70 and RSR-B2 interactions with the TSHR LRD may reflect binding of TSHR-blocking autoantibodies in general.

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Autoimmune Thyroiditis

Fallahi

Ferrari

Antonelli

2021

Encyclopedia of Gerontology and Population Aging

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Crystal structure of the TSH receptor bound to a blocking type TSHR autoantibody

Cited by 98 publications

References 57 publications

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor

Autoimmune Thyroiditis

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