Organization and function of the FKBP52 and FKBP51 genes

Abstract

Best established as components of steroid hormone receptor complexes, it is now clear that the large molecular weight immunophilins, FKBP52 and FKBP51, play important regulatory roles elsewhere in the cell. This review outlines what is known about the organization of the genes, FKBP4 and FKBP5, respectively, encoding these proteins and describes their diverse actions in the nervous system, reproduction, and cancer. The organization of FKBP4 and FKBP5 is very similar among the chordates, and gene expression is influenced by both genetic and epigenetic mechanisms. Recent studies identifying roles of FKBP52 and FKBP51 in the regulation of the microtubule-associated protein tau and microtubule assembly are discussed, as is their interaction with and influence on the transient receptor potential canonical (TRPC) subfamily of ion channel proteins.

Figure 1

Gene organization of FKBP4 and FKBP5. Solid boxes represent exons and horizontal lines represent introns. FKBP4 spans approximately 10 kb, whereas FKBP5 spans approximately 150 kb. The organization of FKBP5 is identical to that of FKBP4 with the exception that non-coding exons 1–3 in FKBP5 are absent in FKBP4. The exon-intron boundaries throughout the two genes are otherwise identical.

Figure 2

Crystallographic structures of FKBP52 (yellow) and FKBP51 (blue). Superimposing the three-dimensional structures of FKBP51 and FKBP52 shows their structural similarity and reveals differences in domain-domain orientations. The PPIase domain at the N-terminus (FK1) and the TPR domain at the C-terminus are oriented differently in the two proteins. From: Proc Natl Acad Sci U S A. 2004 June 1; 101(22): 8348–8353. Published online 2004 May 24. doi: 10.1073/pnas.0305969101.

Figure 3

Model of FKBP51- and FKBP52-mediated regulation of microtubule dynamics. Microtubules are stabilized by the binding of cis tau, but are destabilized when tau becomes phosphorylated and can no longer bind. Phosphorylated tau in a trans configuration can be part of an FKBP51 heterocomplex or an FKBP52 heterocomplex. These heterocomplexes consist of at least FKBP51/FKBP52, phosphorylated trans tau, and Hsp90. In the FKBP51 heterocomplex, the TPR domain of FKBP51 (green) mediates interaction with Hsp90, and its FK1 domain is spatially oriented towards phosphorylated trans tau (yellow). In this orientation, FKBP51 catalyzes isomerization to the cis configuration that allows the phosphatase PP5 access to tau. PP5 dephosphorylates cis tau, which recycles to bind to and stabilize microtubules. In the FKBP52 heterocomplex, while the TPR domain of FKBP52 (blue) mediates binding to Hsp90, its FK1 domain is oriented away from phosphorylated trans tau thereby preventing PPIase activity on tau. Tau remains in a phosphorylated trans configuration unable to bind to microtubules, which leads to microtubule destabilization.