Hormone interactions to Leu-rich repeats in the gonadotropin receptors - I. Analysis of Leu-rich repeats of human luteinizing hormone/chorionic gonadotropin receptor and follicle-stimulating hormone receptor

The luteinizing hormone receptor (LHR) and follicle-stimulating hormone rec eptor (FSHR) have an similar to 350-amino acid-long, N-terminal extracellul ar exodomain, This exodomain binds hormone with high affinity and specifici ty and contains eight to nine putative Leu-rich repeat (LRR) sequences. LRR s are known to assume the horseshoe structure in ribonuclease inhibitors, a nd the inner lining of the horseshoe consists of the P-stranded Leu/Ile-X-L eu/Ile motif. In the case of ribonuclease inhibitors, these beta strands in teract with ribonuclease, However, it is unclear whether the putative LRRs of LHR and FSHR play any role in the structure and function. In this work, the P-stranded Leu/Ile residues in all LRRs of the human LHR and FSHR were Ale-scanned and characterized. In addition, the 23 residues around LRR2 of LHR were Ala-scanned, The results show that beta -stranded Leu and Ile resi dues in all LRRs are important but not equally. These Leu/Ile-X-Leu/Ile mot ifs appear to form the hydrophobic core of the LRR loop, crucial for the LR R structure. Interestingly, the hot spots are primarily in the upstream and downstream LRRs of the LHR exodomain, whereas important LRRs spread throug hout the FSHR exodomain. This may explain the distinct hormone specificity despite the structural similarity of the two receptors.