Disease relevance of FKBP1B

• Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6 [1].
• A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia [2].
• The inotropic adaptation during late preconditioning against myocardial stunning is associated with an increase in FKBP12.6 [3].
• Macrophage infectivity potentiator (CbMip, 23.5 kDa) protein of the obligate intracellular bacterium, Coxiella burnetii, was shown previously to belong to the family of FKBPs based on sequence homology and peptidyl-prolyl cis/trans isomerase (PPIase) activity [4].
• A thorough understanding of the structural basis of RyR2-FKBP12.6 interaction should aid in understanding the roles that have been proposed for FKBP12.6 in heart failure and in certain forms of sudden cardiac death [5].

High impact information on FKBP1B

• We show that protein kinase A (PKA) phosphorylation of RyR2 dissociates FKBP12.6 and regulates the channel open probability (Po) [6].
• PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts [6].
• The first 38 amino-acid residues of porcine PPIase and of bovine cyclophilin are identical and the two proteins both have a relative molecular mass of about 17,000 (ref. 7). The catalysis of prolyl isomerization in oligopeptides and of protein folding by PPIase are strongly inhibited in the presence of low levels of CsA [7].
• Pin1 is a novel essential peptidyl-prolyl isomerase (PPIase) that inhibits entry into mitosis and is also required for proper progression through mitosis, but its substrate(s) and function(s) remain to be determined [8].
• Peptidyl prolyl cis-trans isomerase activity (PPIase) was measured in SF from knee punctures of 26 patients with RA and five patients with knee osteoarthritis (OA) [9].

Chemical compound and disease context of FKBP1B

• In addition, a variety of k(cat)/K(m) values, ranging from 1.1 mM(-1) s(-1) for the B. subtilis PPIase to over 10 mM(-1) s(-1) for human and 13 mM(-1) s(-1) for E. coli, were detected using the common substrate suc-Ala-Ala-Pro-Phe-pNA [10].

Biological context of FKBP1B

• These results support the involvement of FKBP1B gene in the genetic susceptibility to the AITDs development in the studied family [11].
• Previously, we reported a strong evidence of linkage between D2S171 microsatellite marker (located in vicinity of FKBP1B gene) and susceptibility to autoimmune thyroid diseases (AITDs) [11].
• In this study, we report linkage disequilibrium between the dimorphism (C/T) in the 3' untranslated region (3' UTR) of FKBP1B gene and susceptibility to AITDs [11].
• Co-expression of FKBP12.6, but not FKBP12, or incubation of cells with ryanodine suppressed intracellular Ca2+ flux and restored normal cell viability and proliferation [1].
• Localization of the 12.6-kDa FK506-binding protein (FKBP12.6) binding site to the NH2-terminal domain of the cardiac Ca2+ release channel (ryanodine receptor) [12].

Anatomical context of FKBP1B

• Evidence of association between FKBP1B and thyroid autoimmune disorders in a large Tunisian family [11].
• Our results suggest that FKBP12.6 has both a unique physiological role in excitation-contraction coupling in cardiac muscle and the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin [13].
• The microsomes that were then devoid of FKBP12.6 did not show Ca2+ release by cADPR [14].
• In transfected Jurkat cells, FKBP12.6 is equivalent to FKBP12 at mediating the inhibitory effects of FK506 [13].
• The Ca(2+) release channel of human skeletal muscle and cardiac muscle is associated with FK506 binding proteins (FKBP), FKBP12 and FKBP12.6, respectively [15].

Associations of FKBP1B with chemical compounds

• However, in CHO(hRyR2) cells co-expressing FKBP12.6, Ca(2+) release triggered by the addition of 4-chloro- m -cresol was markedly decreased [16].
• Expression of eGFP-tagged RyR constructs encoding distinct transmembrane topological models profoundly altered intracellular Ca(2+) handling and was refractory to modulation by ryanodine, FKBP12.6 and caffeine [17].
• In contrast to the wild-type enzyme, several variants of FKBP12 with greatly reduced PPIase activity were unable to suppress EGF receptor tyrosine kinase significantly [18].
• The proline residue in PPIase substrates at the P1' subsite, which follows the isomerizing peptide bond, appears to be the common recognition element for all subfamilies of this enzyme class [19].
• Generally, PPIase catalysis demonstrated stereospecificity for monofluoro substitutions at the 4-position of the pyrrolidine ring [19].

Physical interactions of FKBP1B

• 6. However, expression of a large RyR2 C-terminal construct in mammalian cells encompassing the pore-forming transmembrane domains exhibits rapamycin-sensitive binding specifically to FKBP12.6 but not to FKBP12 [20].
• We also found that a distinct, alternatively spliced variant of FKBP12.6 was unable to interact with RyR [21].

Regulatory relationships of FKBP1B

• PKA phosphorylation of RyR2 induces dissociation of the regulatory protein FKBP12.6 resulting in channels with increased sensitivity to Ca2+-induced Ca2+ release [22].

Other interactions of FKBP1B

• Our studies suggest that a novel interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a central role in the modulation of this critical ion channel [20].
• Interaction of FKBP12.6 with the cardiac ryanodine receptor C-terminal domain [20].
• RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2) [23].
• After 4-week treatment, CPU0213 was capable to attenuate completely the down-regulated FKBP12.6 and SERCA2a, and up-regulated ET system in association with a recovery of the cardiac insufficiency of diabetic cardiomyopathy [24].
• This review discusses the regulation of RyRs by FKBPs and the possibility that defective modulation of RyR2 by FKBP12.6 could play a role in heart failure, CPVT, and ARVD2 [25].

Analytical, diagnostic and therapeutic context of FKBP1B

• RyR2(T1874-GFP) was purified from cell lysates in a single step by affinity chromatography using GST-FKBP12.6 as the affinity ligand [26].
• Fluorescence in situ hybridization revealed that the FKBP12.6 gene was located on chromosome 2 p21-23, which is different from the locus (chromosome 20 p13) of the FKBP12 gene [27].
• Although the biological function of the truncated version of OTK4 is unknown, both transcripts were ubiquitously expressed in human tissues examined by the reverse-transcriptase PCR (RT-PCR) method [28].
• Infection of guinea pigs showed that strains with dimerization-deficient Mip (JR32-2.4) or a very low PPIase activity (JR32-2.2) were significantly attenuated in the animal model [29].
• We have used cryoelectron microscopy and three-dimensional (3D) reconstruction techniques to determine the binding position of FKBP12.6 on the surface of canine RyR2 [5].

References