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Large-scale, in-cell photocrosslinking at single-residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins
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Large-scale, in-cell photocrosslinking at single-residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins
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Large-scale, in-cell photocrosslinking at single-residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins
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Journal Article
Large-scale, in-cell photocrosslinking at single-residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins
2023
Overview
The Hsp90 co-chaperones FKBP51 and FKBP52 play key roles in steroid-hormone-receptor regulation, stress-related disorders, and sexual embryonic development. As a prominent target, glucocorticoid receptor (GR) signaling is repressed by FKBP51 and potentiated by FKBP52, but the underlying molecular mechanisms remain poorly understood. Here we present the architecture and functional annotation of FKBP51-, FKBP52-, and p23-containing Hsp90–apo-GR pre-activation complexes, trapped by systematic incorporation of photoreactive amino acids inside human cells. The identified crosslinking sites clustered in characteristic patterns, depended on Hsp90, and were disrupted by GR activation. GR binding to the FKBP
FK1
, but not the FKBP
FK2
, domain was modulated by FKBP ligands, explaining the lack of GR derepression by certain classes of FKBP ligands. Our findings show how FKBPs differentially interact with apo-GR, help to explain the differentiated pharmacology of FKBP51 ligands, and provide a structural basis for the development of improved FKBP ligands.
The authors reveal the architecture and functional annotation of large immunophilin-containing Hsp90–apo-GR complexes by systematic incorporation of photocrosslinker inside human cells and show that FKBP51 and FKBP52 differentially interact with the apo-GR.
Publisher
Nature Publishing Group US,Nature Publishing Group
