Integrative model of the FSH receptor reveals the structural role of the flexible hinge region.

Marcus Nagel, Rocco Moretti, Ralf Paschke, Martin von Bergen, Jens Meiler, Stefan Kalkhof

Journal: Structure (London, England : 1993) 2022;30(10):1424-1431.e3

PMID: 35973423

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Abstract

The follicle-stimulating hormone receptor (FSHR) belongs to the glycoprotein hormone receptors, a subfamily of G-protein-coupled receptors (GPCRs). FSHR is involved in reproductive processes such as gonadal development and maturation. Structurally, the extensive extracellular domain, which contains the hormone-binding site and is linked to the transmembrane domain by the hinge region (HR), is characteristic for these receptors. How this HR is involved in hormone binding and signal transduction is still an open question. We combined in vitro and in situ chemical crosslinking, disulfide pattern analysis, and mutation data with molecular modeling to generate experimentally driven full-length models. These models provide insights into the interface, important side-chain interactions, and activation mechanism. The interface indicates a strong involvement of the connecting loop. A major rearrangement of the HR seems implausible due to the tight arrangement and fixation by disulfide bonds. The models are expected to allow for testable hypotheses about signal transduction and drug development for GPHRs.

Address: Department for Molecular Systems Biology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany; Center for Structural Biology, Vanderbilt University, Nashville, TN 37212, USA; Division of Endocrinology, Department of Endocrinology and Nephrology, University Clinic Leipzig, Germany.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37212, USA.; Division of Endocrinology, Department of Endocrinology and Nephrology, University Clinic Leipzig, Germany; Department of Medicine, Division of Endocrinology, Departments of Oncology, Pathology, and Biochemistry and Molecular Biology & Arnie Charbonneau Cancer Institute Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Department for Molecular Systems Biology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany; Institute of Biochemistry, Faculty of Life Sciences, University of Leipzig, Leipzig, Germany.; Center for Structural Biology, Vanderbilt University, Nashville, TN 37212, USA; Leipzig University Medical School, Institute for Drug Discovery, 04103 Leipzig, Germany. Electronic address: [email protected].; Department for Molecular Systems Biology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany; Institute for Bioanalysis, University of Applied Sciences Coburg, Coburg, Germany; Fraunhofer Institute for Cell Therapy and Immunology, Department of Preclinical Development and Validation, 04103 Leipzig, Germany. Electronic address: [email protected].

DOI: 10.1016/j.str.2022.07.007

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MeSH Terms: Disulfides, Follicle Stimulating Hormone, Glycoproteins, Models, Molecular, Receptors, FSH