TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.

Abstract

The TSH receptor (TSHR) on the surface of thyrocytes is unique among the glycoprotein hormone receptors in comprising two subunits: an extracellular A-subunit, and a largely transmembrane and cytosolic B-subunit. Unlike its ligand TSH, whose subunits are encoded by two genes, the TSHR is expressed as a single polypeptide that subsequently undergoes intramolecular cleavage into disulfide-linked subunits. Cleavage is associated with removal of a C-peptide region, a mechanism similar in some respects to insulin cleavage into disulfide linked A- and B-subunits with loss of a C-peptide region. The potential pathophysiological importance of TSHR cleavage into A- and B-subunits is that some A-subunits are shed from the cell surface. Considerable experimental evidence supports the concept that A-subunit shedding in genetically susceptible individuals is a factor contributing to the induction and/or affinity maturation of pathogenic thyroid-stimulating autoantibodies, the direct cause of Graves' disease. The noncleaving gonadotropin receptors are not associated with autoantibodies that induce a "Graves' disease of the gonads." We also review herein current information on the location of the cleavage sites, the enzyme(s) responsible for cleavage, the mechanism by which A-subunits are shed, and the effects of cleavage on receptor signaling.

• Authors: Basil Rapoport, Sandra M McLachlan
• Journal: Endocrine reviews (Endocr Rev) Vol. 37 Issue 2 Pg. 114-34 (Apr 2016) ISSN: 1945-7189 [Electronic] United States
• PMID: 26799472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Protein Subunits
• Receptors, Thyrotropin

Topics

• Animals
• Humans
• Protein Multimerization
• Protein Subunits (genetics, metabolism)
• Protein Transport (genetics)
• Proteolysis
• Receptors, Thyrotropin (genetics, metabolism)
• Thyroid Epithelial Cells (metabolism)