FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity.
The crystal structures of the leucine-rich repeat domain (LRD) of the FSH receptor (FSHR) in complex with FSH and the TSH receptor (TSHR) LRD in complex with the thyroid-stimulating autoantibody (M22) provide opportunities to assess the molecular basis of the specificity of glycoprotein hormone-receptor binding. A comparative model of the TSH-TSHR complex was built using the two solved crystal structures and verified using studies on receptor affinity and activation. Analysis of the FSH-FSHR and TSH-TSHR complexes allowed identification of receptor residues that may be important in hormone-binding specificity. These residues are in leucine-rich repeats at the two ends of the FSHR and the TSHR LRD structures but not in their central repeats. Interactions in the interfaces are consistent with a higher FSH-binding affinity for the FSHR compared with the binding affinity of TSH for the TSHR. The higher binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR compared with hTSH appears not to be dependent on interactions with the TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH interact with the LRD. This suggests that TSHs are likely to interact with other parts of the receptors in addition to the LRD with these non-LRD interactions being responsible for affinity differences. Analysis of interactions in the FSH-FSHR and TSH-TSHR complexes suggests that the alpha-chains of both hormones tend to be involved in the receptor activation process while the beta-chains are more involved in defining binding specificity.
Núñez Miguel
R
R
FIRS Laboratories, RSR Ltd., Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK.
Sanders
J
J
Chirgadze
D Y
DY
Blundell
T L
TL
Furmaniak
J
J
Rees Smith
B
B
D000596:Amino Acids; D000818:Animals; D002417:Cattle; D005640:Follicle Stimulating Hormone / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018828:Immunoglobulins, Thyroid-Stimulating / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011962:Receptors, FSH / Q000737:chemistry / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000378:metabolism*; D013552:Swine
D000596:Amino Acids; D018828:Immunoglobulins, Thyroid-Stimulating; D011962:Receptors, FSH; D011989:Receptors, Thyrotropin; D005640:Follicle Stimulating Hormone