Disease relevance of FKBP2

• Exclusion of the 13-kDa rapamycin binding protein gene (FKBP2) as a candidate gene for multiple endocrine neoplasia type 1 [1].
• Northern studies have revealed that FKBP2 is expressed in those tissues predisposed to hyperplasia in MEN1; however, single-strand conformation polymorphism analysis and direct sequencing of DNAs from affected members of MEN1 kindreds and sporadic tumour DNAs have been performed and no mutations have been found [1].
• The putative peptidylprolyl cis-trans isomerase (PPIase) encoded by XC2699 of the plant bacterial pathogen Xanthomonas campestris pv. campestris 8004 exhibits a 49% similarity at the amino-acid level to the Mip protein of Legionella pneumophila [2].
• This mip-like gene, XC2699, was overexpressed in Escherichia coli and the purified (His)6-tagged Mip-like protein encoded by XC2699 exhibited a PPIase activity specifically inhibited by FK-506 [2].

High impact information on FKBP2

• The 13-kD FK506 binding protein, FKBP13, interacts with a novel homologue of the erythrocyte membrane cytoskeletal protein 4.1 [3].
• Interestingly, FKBP13 cofractionates with the red blood cell homologue of 4.1 (4.1R) in ghosts, inside-out vesicles, and Triton shell preparations [3].
• The association was confirmed by immunoprecipitation of both endogenous BIG1 and FKBP13 from Jurkat T cells with antibodies against either one [4].
• These findings are consistent with a role for FKBP13 and FK506 in vesicular trafficking, influencing ARF activity through their guanine nucleotide-exchange proteins [4].
• Yeast two-hybrid screens of a human placenta cDNA library with BIG1 cDNA constructs revealed specific interaction of the N-terminal region (amino acids 1-331) with FK506-binding protein 13 (FKBP13) [4].

Biological context of FKBP2

• 1. In this study, we report the physical localisation of the 13-kDa FK506 and rapamycin binding protein gene (FKBP2) to the cosmid marker D11S750, which is located inside the MEN1 region of non-recombination [1].
• FKBP2 is three kb in length and contains six exons [5].
• The conserved residues that comprise the drug binding site and rotamase active site of FKBP-12 are completely conserved in FKBP-13 [6].
• Together, these data suggest a role for FKBP13 in ER protein folding [7].
• The function of the immunophilins, FKBP 12 and FKBP 13, which are binding proteins for the immunosuppressant drug FK506 and rapamycin, remains poorly defined, although it has been suggested that immunophilins and immunophilin-like proteins may play a role in protein sorting/folding and intracellular calcium ion regulation [8].

Anatomical context of FKBP2

• Although no internal hydrophobic region, and thus no transmembrane domain, is apparent within the 120 amino acids of mature FKBP-13, a potential endoplasmic reticulum retention sequence (Arg-Thr-Glu-Leu) is found at its C terminus [6].
• By immunofluorescence, the overexpressed cDNA for FKBP 13 in Hela cells gave an ER-staining pattern highly similar to that of known ER proteins [8].
• As a first step towards understanding the function of FKBP 13, we studied its subcellular localization by immunoblotting of well-defined subcellular fractions from a canine pancreatic homogenate and immunocytochemical analysis of an overexpressed cloned cDNA for FKBP 13 [8].
• Further analysis of the calf thymus protein revealed a peptide with homology to a region near the COOH terminus of both FKBP-12 and FKBP-13 [9].
• Recent research has uncovered a new paradigm in which an immunophilin, FKBP13, and potentially other enzymes of the chloroplast thylakoid lumen are oxidatively activated in the light (2SH-->S-S) [10].

Associations of FKBP2 with chemical compounds

• Separation of the ER luminal contents and membrane revealed FKBP 13 to be a luminal ER protein [8].
• Actinomycin D chase experiments in ionomycin-treated cells revealed no change in the half-life of FKBP13 mRNA, indicating that the increase in FKBP13 mRNA observed was not due to greater message stability [7].
• Moreover, FKBP 13 co-banded with the ER markers on isopycnic sucrose gradients [8].
• By Northern-blot analysis, tunicamycin resulted in a 2-fold rise in FKBP13 mRNA, whereas ionophores (A23187 and ionomycin) caused a more impressive rise in FKBP13 mRNA (up to 5-fold with ionomycin) [7].
• The Hsp56 component of steroid receptor complexes binds to immobilized FK506 and shows homology to FKBP-12 and FKBP-13 [9].

Physical interactions of FKBP2

• RESULTS: The C-chain of complement C1q (C1q-C) was detected to interact with FKBP13 in the yeast two-hybrid system and in a protein complementation assay [11].

Other interactions of FKBP2

• Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13 [6].
• These studies exclude FKBP2 as a candidate gene for MEN1 [1].
• Although etiolated leaves produced detectable levels of cyclophilin B/C, they did not express FKBP13 [12].
• In a yeast two-hybrid screen FKBP13, a member of the FK506 Binding Protein (FKBP) family, was detected to interact with the serpin alpha-1-antichymotrypsin (ACT) [13].
• Binding of C1q-C to FKBP13 could not be prevented in the presence of FK506, demonstrating that possibly other regions than the binding pocket of the drug are responsible for the interaction of the two proteins [11].

Analytical, diagnostic and therapeutic context of FKBP2

• Here we report the molecular cloning and subcellular localization of a 13-kDa FKBP (FKBP-13), which has a 21-amino acid signal peptide and appears to be membrane-associated [6].
• In situ hybridization studies reveal cellular colocalizations for FKBP13 and 4.1G-CTD throughout the body during development, supporting a physiologic role for the interaction [3].
• These observations lead us to speculate that "Hsp56" may mediate immunosuppression and inhibition of T-cell proliferation by FK506 and may do so via a cytosolic signal transduction pathway separate, but not necessarily exclusive, from that of FKBP-12 and FKBP-13 [9].
• We have examined the role of the key surface residues of FKBP12 and FKBP13 in calcineurin interactions by generating substitutions at these residues by site-directed mutagenesis [14].

References