Editors' ChoiceStructural Biology

Inducing Conformational Change in the Ligand

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Science Signaling  07 Aug 2012:
Vol. 5, Issue 236, pp. ec207
DOI: 10.1126/scisignal.2003473

Follicle-stimulating factor (FSH) is a canonical glycoprotein hormone that forms heterodimers consisting of an α subunit common to all glycoprotein hormones and a hormone-specific β subunit. Glycoprotein hormone receptors are G protein–coupled receptors (GPCRs) that have large ectodomains comprising a rigid hormone-binding domain at the N terminus and a “hinge” domain responsible for linking hormone binding to receptor activation. In the FSH receptor, Tyr335 must be sulfated for hormone recognition and signaling. Jiang et al. solved the crystal structure of FSH in complex with the ectodomain of FSH receptor (FSHR), which contained 12 leucine-rich repeats (LRRs) and a protruding hairpin loop. LRR1 through 10 comprised the hormone-binding domain. Contrary to expectation, the authors discovered that the hinge domain was not a separate or disordered domain but comprised LRR11 and 12 along with a protruding hairpin loop in between them that contained Tyr335, which was sulfated in the structure. The presence of three disulfide bonds between the hairpin loop; the CF3 motif, which is common to GPCRs; and hydrophobic interactions that coupled the hinge domain to the hormone-binding domain suggested that large-scale conformational changes upon ligand binding were unlikely. At the hormone-receptor interface, sulfated Tyr335 of the FSHR ectodomainwas inserted into a pocket on FSH lined with hydrophobic residues and the positively charged Arg35 of FSH. This microenvironment resulted in a charge-charge interaction between sulfated Tyr335 of FSHRectodomain and Arg35 of FSH. Comparison with the structure of free FSH revealed that FSH changed conformation to accommodate this interaction. The receptor-binding conformation of FSH was also seen in a structure of FSH in complex with a fragment of the FSHR that only contained the hormone-binding domain, suggesting that the presence of the receptor’s sulfated residue was not necessary to induce this change in ligand conformation. Mutation of a residue on FSH below the tyrosine binding pocket from phenylalanine to glutamate, which should alter the interaction with the sulfated Tyr335 of the receptor, enhanced FSHR signaling as measured in a β-arrestin recruitment assay and an estradiol production assay. These structural data suggest that the receptor recruits FSH, inducing conformational changes in FSH that open a binding pocket for sulfated Tyr335 from FSHR. Insertion of the sulfated Tyr335 would then lead to receptor activation and signaling.

X. Jiang, H. Liu, X. Chen, P.-H. Chen, D. Fischer, V. Sriraman, H. N. Yu, S. Arkinstall, X. He, Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc. Natl. Acad. Sci. U.S.A. 109, 12491–12496 (2012). [Abstract] [Full Text]

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