The multimerization pathway of the glucocorticoid receptor

Estebanez-Perpina, E.; Alegre-Marti, A.; Jimenez-Panizo, A.; Lafuente, A.; Johnson, T. A.; Montoya-Novoa, I.; Abella, M.; Perez, P.; Fernandez-Recio, J.; Presman, D. M.; Hager, G. L.; Fuentes-Prior, P.

doi:10.1101/2024.12.12.628195

bioRxiv · 10.1101/2024.12.12.628195

The multimerization pathway of the glucocorticoid receptor

Estebanez-Perpina, E.·Alegre-Marti, A.·Jimenez-Panizo, A.·Lafuente, A.·Johnson, T. A.·Montoya-Novoa, I.·Abella, M.·Perez, P.·Fernandez-Recio, J.·Presman, D. M.·Hager, G. L.·Fuentes-Prior, P.

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Abstract

The glucocorticoid receptor (GR) is a leading drug target due to its anti-inflammatory and immunosuppressive roles. The functional oligomeric conformation of full-length GR (FL-GR), which is key for its biological activity, remains disputed. Here we present a new crystal structure of agonist-bound GR ligand-binding domain (GR-LBD) comprising eight copies of a non-canonical dimer. The biological relevance of this dimer for receptor multimerization in living cells has been verified by studying single-and double-point mutants of FL-GR in fluorescence microscopy (Number & Brightness) and transcriptomic analysis. Self-association of this GR-LBD basic dimer in two mutually exclusive assemblies reveals clues for FL-GR multimerization and activity in cells. We propose a model for the structure of multidomain GR based on our new data and suggest a detailed oligomerization pathway. This model reconciles all currently available structural and functional information and provides a more comprehensive understanding of the rare glucocorticoid resistance disorder (Chrousos syndrome).

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Estebanez-Perpina, E., Alegre-Marti, A., Jimenez-Panizo, A., Lafuente, A., Johnson, T. A., Montoya-Novoa, I., Abella, M., Perez, P., Fernandez-Recio, J., Presman, D. M., Hager, G. L., Fuentes-Prior, P.. 2024-12-12. The multimerization pathway of the glucocorticoid receptor. https://doi.org/10.1101/2024.12.12.628195

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