The Many Faces of FKBP51

Abstract

The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated in several cellular pathways and numerous interacting protein partners have been reported. However, no consensus on the underlying molecular mechanisms has yet emerged. Here, we review the protein interaction partners reported for FKBP51, the proposed pathways involved, their relevance to FKBP51’s physiological function(s), the interplay with other FKBPs, and implications for the development of FKBP51-directed drugs.

Post-translational modifications and stress adaptation: the paradigm of FKBP51

“…The stress protein FKBP51, promoted through translational research FKBP51 is a show-case of translational research where clinical and basic science approaches stimulated each other. The background of FKBP51 is laid out here only shortly, and the reader is referred to the numerous recent reviews for more detailed information [10][11][12][13][14][15]. Originally discovered as part of steroid receptor-heat shock protein 90 hetero-complexes, FKBP51 was shown to be a potent inhibitor of GR by several laboratories [16][17][18][19].…”

“…Biochemically, FKBP51 is able to isomerize peptidyl-prolyl bonds [20]; the physiological relevance, if any, of this function is not clear [11,12,21]. However, the peptidylprolyl isomerase domain of FKBP51 is engaged in protein interactions, and drug binding to this domain likely affects several functions of this protein [13].…”

“…Later, FKBP5 could be linked to additional stress-related diseases such as post-traumatic stress disorder [12,14]. These findings strongly amplified the interest in FKBP51 and stimulated research on its function and regulation in several laboratories; this greatly expanded the knowledge base on FKBP51's ( patho)physiological role, regulation on several levels and involvement in multiple molecular pathways, going beyond stress regulation [12,13]. The variety of its physiological functions goes along with its association with several proteins, including proteins involved in writing and erasing PTMs, as detailed in the subsequent sections.…”

FKBP51 induces p53‑dependent apoptosis and enhances drug sensitivity of human non‑small‑cell lung cancer cells

“…FK506-binding protein 51 (FKBP51) is a member of the immunophilin family that is involved in multiple signaling pathways, tumorigenesis and chemoresistance (4,5). As a genetic factor regulating the hypothalamic-pituitary-adrenal (HPA) axis, FKBP51 plays an important role in stress regulation (6,7).…”

MCMBP maintains genome integrity by protecting the MCM subunits from degradation

“…FKBP51, a co-factor for HSP90, associates with MCMBP independently of 18 HSP90 (Taipale et al 2014). FKBP51 displays peptidyl-prolyl isomerase activity, which 19 helps to promote structural changes in its substrates(Hahle et al 2019). We 20 hypothesize that MCMBP acts together with FKBP51 to promote the formation of 21 MCM2-7 hexamers in the nucleus.…”