Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

Miguel, Ricardo Núñez; Sanders, Jane; Chirgadze, Dimitri Y.; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1677/jme-08-0152

Cited by 33 publications

(19 citation statements)

References 60 publications

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“…Despite M22 and TSH both interfacing with overlapping regions on the concave surface of the TSHR LRD, the orientation of the two ligands is very different. TSH and FSH are elongated molecules that bind transversely to the LRD, partially wrapping around the LRD as in a hand clasp [5], [24]. M22 on the other hand binds in a more perpendicular manner to the LRD [6].…”

Section: Discussionmentioning

confidence: 99%

Novel Information on the Epitope of an Inverse Agonist Monoclonal Antibody Provides Insight into the Structure of the TSH Receptor

et al. 2012

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The TSH receptor (TSHR) comprises an extracellular leucine-rich domain (LRD) linked by a hinge region to the transmembrane domain (TMD). Insight into the orientation of these components to each other is required for understanding how ligands activate the receptor. We previously identified residue E251 at the LRD-hinge junction as contributing to coupling TSH binding with receptor activation. However, a single residue cannot stabilize the LRD-hinge unit. Therefore, based on the LRD crystal structure we selected for study four other potential LRD-hinge interface charged residues. Alanine substitutions of individual residues K244, E247, K250 and R255 (as well as previously known E251A) did not affect TSH binding or function. However, the cumulative mutation of these residues in varying permutations, primarily K250A and R255A when associated with E251A, partially uncoupled TSH binding and function. These data suggest that these three residues, spatially very close to each other at the LRD base, interact with the hinge region. Unexpectedly and most important, monoclonal antibody CS-17, a TSHR inverse agonist whose epitope straddles the LRD-hinge, was found to interact with residues K244 and E247 at the base of the convex LRD surface. These observations, together with the functional data, exclude residues K244 and E247 from the TSHR LRD-hinge interface. Further, for CS-17 accessibility to K244 and E247, the concave surface of the TSHR LRD must be tilted forwards towards the hinge region and plasma membrane. Overall, these data provide insight into the mechanism by which ligands either activate the TSHR or suppress its constitutive activity.

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Section: Discussionmentioning

confidence: 99%

Novel Information on the Epitope of an Inverse Agonist Monoclonal Antibody Provides Insight into the Structure of the TSH Receptor

et al. 2012

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“…As described previously, binding of the human thyroid-stimulating autoantibody M22 mimics the binding of TSH to the TSHR (Nú ñez Miguel et al 2009). The M22 LC mimics the binding of the TSHb chain as both interact with the 1st, 2nd, 4th, 6th, 7th, 8th, 9th and 10th repeats of TSHR260.…”

Section: Analysis Of the Tshr260-k1-70 Fab Tshr260-m22 Fab (Sanders mentioning

confidence: 99%

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

Sanders¹,

Young²,

Sanders³

et al. 2011

Journal of Molecular Endocrinology

157

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A complex of the TSH receptor extracellular domain (amino acids 22-260; TSHR260) bound to a blocking-type human monoclonal autoantibody (K1-70) was purified, crystallised and the structure solved at 1 . 9 Å resolution. complexes show a root mean square deviation on all C a atoms of only 0 . 51 Å . These high-resolution crystal structures provide a foundation for developing new strategies to understand and control TSHR activation and the autoimmune response to the TSHR.

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“…The large orthosteric site of the TSHR has multiple binding domains for autoantibodies [68] and TSH [69]. Clearly, stimulation or blockade of all such binding sites could not be achieved with one small molecule and so effective small molecules are more likely to activate or derail the signaling pathways rather than influencing the ligand–receptor interaction.…”

Section: Mechanism Of Small Molecule Actionmentioning

confidence: 99%

Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

Davies¹,

Latif²

2015

Expert Opinion on Therapeutic Targets

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Introduction The thyroid-stimulating hormone receptor (TSHR) is the essential molecule for thyroid growth and thyroid hormone production. Since it is also a key autoantigen in Graves’ disease and is involved in thyroid cancer pathophysiology, the targeting of the TSHR offers a logical model for disease control. Areas covered We review the structure and function of the TSHR and the progress in both small molecule ligands and TSHR antibodies for their therapeutic potential. Expert opinion Stabilization of a preferential conformation for the TSHR by allosteric ligands and TSHR antibodies with selective modulation of the signaling pathways is now possible. These tools may be the next generation of therapeutics for controlling the pathophysiological consequences mediated by the effects of the TSHR in the thyroid and other extrathyroidal tissues.

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Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

Cited by 33 publications

References 60 publications

Novel Information on the Epitope of an Inverse Agonist Monoclonal Antibody Provides Insight into the Structure of the TSH Receptor

Novel Information on the Epitope of an Inverse Agonist Monoclonal Antibody Provides Insight into the Structure of the TSH Receptor

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

Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

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