Alternative titles; symbols
HGNC Approved Gene Symbol: FKBP1B
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38): 2:24,033,206-24,063,681 (from NCBI)
For background information on FK506-binding proteins (FKBPs), see FKBP1A (186945).
Arakawa et al. (1994) isolated a novel gene encoding a protein closely related to human FKBPs from a human fetal brain cDNA library. The full-length cDNA encoded an open reading frame of 108 amino acids with 88% identity in predicted amino acid sequence to FKBP12 (186945). The FKBP1L gene, designated OTK4 by the authors, also had sequence similarity with other FKBPs in species ranging from prokaryotes to humans, including FKPB13 (186946), FKBP25 (186947), and FKBP52 (600611). The authors also found an alternatively spliced transcript that contained a 45-bp insertion which included a stop codon. Both transcripts were ubiquitously expressed in several human tissues examined by RT-PCR.
Arakawa et al. (1994) found that recombinant FKBP1L protein produced in E. coli showed peptidyl-prolyl cis-trans isomerase activity like that of other FKBPs.
The ryanodine receptor on the sarcoplasmic reticulum is the major source of calcium required for cardiac muscle excitation-contraction coupling. The channel is a tetramer composed of 4 RYR2 (180902) polypeptides and 4 FK506-binding proteins (FKBP12.6). Marx et al. (2000) showed that protein kinase A (PKA; see 176911) phosphorylation of RYR2 dissociates FKBP12.6 and regulates the channel open probability. Using cosedimentation and coimmunoprecipitation, the authors defined a macromolecular complex composed of RYR2, FKBP12.6, PKA, the protein phosphatases PP1 (see 603771) and PP2A (see 603113), and an anchoring protein, AKAP6 (604691). In failing human hearts, Marx et al. (2000) showed that RYR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to calcium-induced activation.
Using a quantitative yeast 2-hybrid system, Tiso et al. (2002) analyzed and compared the interaction between FKBP12.6 and 3 mutated FKBP12.6 binding regions. An RYR2 mutation (R2474S; 180902.0002) causing catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) markedly increased the binding of RYR2 to FKBP12.6, whereas other RYR2 mutations (N2386I, 180902.0005; Y2392C) significantly decreased this binding. Tiso et al. (2002) suggested that some mutations increase RYR2-mediated calcium release to the cytoplasm, whereas others do not significantly affect cytosolic calcium levels, and that this might explain the clinical differences among patients.
Wehrens et al. (2003) found that during exercise, RYR2 phosphorylation by PKA partially dissociated FKBP12.6 from the RYR2 channel, increasing intracellular Ca(2+) release and cardiac contractility. Fkbp12.6 -/- mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that caused sudden cardiac death. Mutations in RYR2 linked to exercise-induced arrhythmias in patients with CPVT1 reduced the affinity of FKBP12.6 for RYR2 and increased single-channel activity under conditions that simulated exercise. These data suggested that 'leaky' RYR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT1.
Lehnart et al. (2004) reviewed the RYR2-FKBP1B interaction and its role in heart failure and genetic forms of arrhythmias.
Stumpf (2024) mapped the FKBP1B gene to chromosome 2p23.3 based on an alignment of the FKBP1B sequence (GenBank AF322070) with the genomic sequence (GRCh38).
Xin et al. (2002) generated mice deficient in FKBP12.6 by targeted disruption. Male mutant mice had cardiac hypertrophy, but not females. Female hearts were normal despite the fact that male and female knockout mice displayed similar dysregulation of calcium release, seen as increases in the amplitude and duration of calcium sparks and calcium-induced calcium release gain. Female Fkbp12.6-null mice treated with tamoxifen, an estrogen receptor antagonist, developed cardiac hypertrophy similar to that of male mice. Xin et al. (2002) concluded that FKBP12.6 modulates cardiac excitation-contraction coupling and that estrogen plays a protective role in the hypertrophic response of the heart to calcium dysregulation.
In animals with heart failure and in patients with inherited forms of exercise-induced sudden cardiac death, depletion of the channel-stabilizing protein FKBP12.6, which Wehrens et al. (2004) called calstabin-2, from the ryanodine receptor-calcium release channel complex causes an intracellular calcium leak that can trigger fatal cardiac arrhythmias. Using a mouse cardiac arrhythmia model, Wehrens et al. (2004) showed that a derivative of 1,4-benzothiazepine increased the affinity of calstabin-2 for RYR2, which stabilized the closed state of RYR2 and prevented the calcium leak that triggers arrhythmias. They postulated that enhancing the binding of calstabin-2 to RYR2 may be a therapeutic strategy for common ventricular arrhythmias.
Arakawa, H., Nagase, H., Hayashi, N., Fujiwara, T., Ogawa, M., Shin, S., Nakamura, Y. Molecular cloning and expression of a novel human gene that is highly homologous to human FK506-binding protein 12kDa (hFKBP-12) and characterization of two alternatively spliced transcripts. Biochem. Biophys. Res. Commun. 200: 836-843, 1994. [PubMed: 7513996] [Full Text: https://doi.org/10.1006/bbrc.1994.1527]
Lehnart, S. E., Wehrens, X. H. T., Marks, A. R. Calstabin deficiency, ryanodine receptors, and sudden cardiac death. Biochem. Biophys. Res. Commun. 322: 1267-1279, 2004. [PubMed: 15336974] [Full Text: https://doi.org/10.1016/j.bbrc.2004.08.032]
Marx, S. O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., Marks, A. R. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101: 365-376, 2000. [PubMed: 10830164] [Full Text: https://doi.org/10.1016/s0092-8674(00)80847-8]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/04/2024.
Tiso, N., Salamon, M., Bagattin, A., Danieli, G. A., Argenton, F., Bortolussi, M. The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations. Biochem. Biophys. Res. Commun. 299: 594-598, 2002. [PubMed: 12459180] [Full Text: https://doi.org/10.1016/s0006-291x(02)02689-x]
Wehrens, X. H. T., Lehnart, S. E., Huang, F., Vest, J. A., Reiken, S. R., Mohler, P. J., Sun, J., Guatimosim, S., Song, L.-S., Rosemblit, N., D'Armiento, J. M., Napolitano, C., Memmi, M., Priori, S. G., Lederer, W. J., Marks, A. R. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 113: 829-840, 2003. [PubMed: 12837242] [Full Text: https://doi.org/10.1016/s0092-8674(03)00434-3]
Wehrens, X. H. T., Lehnart, S. E., Reiken, S. R., Deng, S.-X., Vest, J. A., Cervantes, D., Coromilas, J., Landry, D. W., Marks, A. R. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 304: 292-296, 2004. [PubMed: 15073377] [Full Text: https://doi.org/10.1126/science.1094301]
Xin, H.-B., Senbonmatsu, T., Cheng, D.-S., Wang, Y.-X., Copello, J. A., Ji, G.-J., Collier, M. L., Deng, K.-Y., Jeyakumar, L. H., Magnuson, M. A., Inagami, T., Kotlikoff, M. I., Fleischer, S. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature 416: 334-337, 2002. [PubMed: 11907581] [Full Text: https://doi.org/10.1038/416334a]