RESUMO
The FK506-binding protein 51 (FKBP51) is a high-molecular-weight immunophilin that emerged as an important drug target for stress-related disorders, chronic pain, and obesity. It has been implicated in a plethora of molecular pathways but remains best characterized as a co-chaperone of Hsp90 in the steroid hormone receptor (SHR) maturation cycle. However, the mechanistic and structural basis for the regulation of SHRs by FKBP51 and the usually antagonistic function compared with its closest homolog FKBP52 remains enigmatic. Here we review recent structural and biochemical studies of FKBPs as regulators in the Hsp90 machinery. These advances provide important insights into the roles of FKBP51 and FKBP52 in SHR regulation.
RESUMO
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 FKBPFK1, but not the FKBPFK2, 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.