Sti1/Hop is a modular protein required for the transfer of client proteins from the Hsp70 to the Hsp90 chaperone system in eukaryotes. It binds Hsp70 and Hsp90 simultaneously via TPR (tetratricopeptide repeat) domains. Sti1/Hop contains three TPR domains (TPR1, TPR2A and TPR2B) and two domains of unknown structure (DP1 and DP2). We show that TPR2A is the high affinity Hsp90-binding site and TPR1 and TPR2B bind Hsp70 with moderate affinity. The DP domains exhibit highly homologous a-helical folds as determined by NMR. These, and especially DP2, are important for client activation in vivo. The core module of Sti1 for Hsp90 inhibition is the TPR2A-TPR2B segment. In the crystal structure, the two TPR domains are connected via a rigid linker orienting their peptide-binding sites in opposite directions and allowing the simultaneous binding of TPR2A to the Hsp90 C-terminal domain and of TPR2B to Hsp70. Both domains also interact with the Hsp90 middle domain. The accessory TPR1-DP1 module may serve as an Hsp70-client delivery system for the TPR2A-TPR2B-DP2 segment, which is required for client activation in vivo.

FKBP51 and FKBP52 are diverse regulators of steroid hormone receptor signaling including regulation of receptor maturation, hormone binding, and nuclear translocation. Although structurally similar, they are functionally divergent, which is largely attributed to differences in the FK1 domain and the proline-rich loop. FKBP51 and FKBP52 have emerged as likely contributors to a variety of hormone-dependent diseases including stress-related diseases, immune function, reproductive functions and a variety of cancers. In addition, recent studies have implicated FKBP51 and FKBP52 in Alzheimer’s disease and other protein aggregation disorders. This review summarizes our current understanding of FKBP51 and FKBP52 interactions within the receptor-chaperone complex, their contributions to health and disease, and their potential as therapeutic targets for the treatment of these diseases.

Embryo implantation in the uterus is a critical step in mammalian reproduction, requiring preparation of the uterus receptive to blastocyst implantation. Uterine receptivity, also known as the window of implantation, lasts for a limited period, and it is during this period blastocysts normally implant. Ovarian steroid hormones estrogen and progesterone (P 4) are the primary regulators of this process. The immunophilin FKBP52 serves as a cochaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues. Here we show a critical role for FKBP52 in mouse implantation. This immunophilin has unique spatiotemporal expression in the uterus during implantation, and females missing the Fkbp52 gene have complete implantation failure due to lack of attainment of uterine receptivity. The overlapping uterine expression of FKBP52 with nuclear progesterone receptor (PR) in wild-type mice together with reduced P 4 binding to PR, attenuated PR transcriptional activity and down-regulation of several P4-regulated genes in uteri of Fkbp52 ؊/؊ mice, establishes this cochaperone as a critical regulator of uterine P4 function. Interestingly, ovulation, another P4-mediated event, remains normal. Collectively, the present investigation provides evidence for an in vivo role for this cochaperone in regulating tissue-specific hormone action and its critical role in uterine receptivity for implantation.mouse ͉ uterus ͉ ovulation ͉ blastocyst ͉ progesterone receptor P rogesterone (P 4 ) is essential for implantation and pregnancy maintenance in all mammalian species studied. In mice, P 4 priming of the uterus is obligatory for estrogen to prepare the uterus to the receptive state conducive to blastocyst implantation. P 4 acting through the nuclear P 4 receptor (PR) modulates uterine physiology and expression of various genes that are required for implantation (1, 2). Numerous defects in mice lacking the Pgr gene that encodes PR include failure in ovulation, mammary gland development, and sexual behavior along with uterine hyperplasia and inflammation, reflecting the critical role of P 4 in female reproduction (3). Appropriate functioning of nuclear steroid hormone receptors depends on interactions with the molecular chaperone machinery to maintain a functional state competent for hormone binding and subsequent transcriptional activation. Functionally mature steroid receptor complexes consist of a receptor monomer, a 90-kDa heat shock protein (Hsp90) dimer, the cochaperone p23, and one of four cochaperones that contain a tetratricopeptide repeat (TPR) domain. The TPR cochaperones include two members of the FK506 binding family of immunophilins, FKBP52͞FKBP4 and FKBP51͞FKBP5, a member of the cyclosporin-binding immunophilin cyclophilin 40 (CyP40) or the protein phosphatase PP5. FKBP52 and FKBP51 are similar to other FKBP family members in that both contain an active peptidylprolyl cis͞trans isomerase domain that catalyzes conformational changes in protein substrates (4, 5).Roles for Hsp90 and p23 in initia...

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