Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52

Abstract

Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to the regulation of the biological functions of several client-proteins. Among these Hsp90-binding immunophilins, there are two highly homologous members named FKBP51 and FKBP52 (FK506-binding protein of 51-kDa and 52-kDa, respectively) that were first characterized as components of the Hsp90-based heterocomplex associated to steroid receptors. Afterwards, they emerged as likely contributors to a variety of other hormone-dependent diseases, stress-related pathologies, psychiatric disorders, cancer, and other syndromes characterized by misfolded proteins. The differential biological actions of these immunophilins have been assigned to the structurally similar, but functionally divergent enzymatic domain. Nonetheless, they also require the complementary input of the TPR domain, most likely due to their dependence with the association to Hsp90 as a functional unit. FKBP51 and FKBP52 regulate a variety of biological processes such as steroid receptor action, transcriptional activity, protein conformation, protein trafficking, cell differentiation, apoptosis, cancer progression, telomerase activity, cytoskeleton architecture, etc. In this article we discuss the biology of these events and some mechanistic aspects.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…This family of molecular chaperones comprises peptidyl-prolyl isomerases, which regulate protein folding by catalyzing the cis/trans transitions at the pyrrolidine heterocycle of L-prolines integrated into a peptide bond [48,175]. Immunophilins can assist the HSP70/HSP90 chaperone machine in client protein folding (see the lower path in Figure 2 and [48][49][50]175]). Immunophilins are traditionally divided into two subfamilies according to their diverse capacity to bind certain immunosuppressive drugs: (i) FK506-binding proteins (FKBPs and FK506-binding protein-like or FKBPL) and (ii) cyclosporin-binding cyclophilins.…”

“…Immunophilins are traditionally divided into two subfamilies according to their diverse capacity to bind certain immunosuppressive drugs: (i) FK506-binding proteins (FKBPs and FK506-binding protein-like or FKBPL) and (ii) cyclosporin-binding cyclophilins. Most immunophilins are in the cytosol [48,175], but cyclophilin D is localized to the mitochondrial matrix and performs very specific functions of controlling the mitochondrial permeability transition pore and regulating electron transport chain behavior [176]. The other peptidyl-prolyl isomerase, protein never in mitosis gene A interacting-1 (PIN1), is an immunophilin-like chaperone protein, which isomerizes phospho-serine/threonine-proline motifs only [177]; this is an example of site-directed chaperoning, which is dependent on the site-specific phosphorylation of a protein substrate.…”

“…Functioning as chaperones, peptidyl-prolyl isomerases control protein conformations and protein trafficking, steroid receptor action, activities of the transcription factor NFκB and hTERT telomerase, Akt/mTOR signaling cascade etc; due to their chaperone function, peptidyl-prolil isomerases are involved in the regulation of the cytoskeleton, apoptosis, cell cycle, and cell differentiation [175]. Meanwhile, FKBP51, FKBP52, and PIN1 can play an important role in onocogenesis and tumor resistance to therapeutics [48,175,177]. In contrast, FKBPL has been characterized as an antitumor protein; its peptide derivatives (AD-01 and ALM201) were taken for preclinical and clinical trials and demonstrated quite encouraging results in CSC-related models [178][179][180].…”

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].…”

“…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]. By virtue of its binding to immune suppressive drugs such as FK506, FKBP51 also has been classified as 'immunophilin' [15]. Biochemically, FKBP51 is able to isomerize peptidyl-prolyl bonds [20]; the physiological relevance, if any, of this function is not clear [11,12,21].…”