FKBP12 associates tightly with the skeletal muscle type 1 ryanodine receptor, but not with other intracellular calcium release channels

Carmody, Mark; Mackrill, John J.; Sorrentino, Vincenzo; O’Neill, Cora

doi:10.1016/s0014-5793(01)02787-9

Cited by 49 publications

(44 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The DHPR copurifies with, and is a substrate of, calcineurin (Sacchetto et al 2002). In addition, Carmody et al (2001) showed that the RyR1 isoform in skeletal muscle tightly associates with the FK506 binding protein FKBP12. FKBP12 is the target of the calcineurin inhibitors FK506 and cyclosporine.…”

Section: Calcineurin Distribution In the Cytoplasm During Muscle Devementioning

confidence: 99%

Calcineurin Localization in Skeletal Muscle Offers Insights into Potential New Targets

Torgan

Daniels

2006

J Histochem Cytochem.

View full text Add to dashboard Cite

/calmodulin-activated protein phosphatase, calcineurin, is believed to regulate the development and function of skeletal and cardiac muscle. Striated muscle contains many calcineurin substrates, a few of which have been colocalized or found in molecular complexes with calcineurin. We examined the subcellular distribution of calcineurin in developing rat skeletal muscle cells and adult mouse skeletal muscle fibers by immunofluorescence microscopy. We found low levels of calcineurin immunoreactivity in the cytoplasm of myoblasts and higher levels in cytoplasmic vesicles of myotubes. Most of these vesicles were not immunoreactive for ryanodine receptors and, those that were, represented a small fraction of nascent triad junctions. In adult myofibers, calcineurin was largely associated with triads. Weaker calcineurin immunoreactivity occurred in the sarcoplasmic reticulum at the level of the M line. Unexpectedly, we found tiny clusters of calcineurin associated with nucleoli of developing myofiber nuclei. There were one to three clusters per nucleolus, either within or at the edges of fibrillar centers where ribosomal genes are transcribed. This suggests a role for calcineurin in regulating ribosome synthesis. Our findings suggest a variety of potential new targets and pathways through which calcineurin could regulate skeletal muscle development and plasticity and underscore the importance of spatial specificity in this regulation. (J Histochem Cytochem 54:119-128, 2006)

show abstract

Section: Calcineurin Distribution In the Cytoplasm During Muscle Devementioning

confidence: 99%

Calcineurin Localization in Skeletal Muscle Offers Insights into Potential New Targets

Torgan

Daniels

2006

J Histochem Cytochem.

View full text Add to dashboard Cite

show abstract

“…In these experiments, the FKBP and pc-MycRyR2C plasmids were co-expressed in HEK293 cells, and evidence for binding was monitored by assaying the amount of FKBP cosedimenting with the microsomal membrane fraction. Centrifugation-based binding assays are often used in situations of rapid ligand dissociation and low affinity, because the receptor and ligand remain in equilibrium throughout the separation period, and they have been used for the study of the RyR-FKBP association (27,29,43,44), as well as the RyR-calmodulin interaction (45). In addition, the assay takes place in a detergent-free environment where the RyR2 C-terminal fragment is most likely to retain a native conformation.…”

Section: Ryr2 C-terminal Fragments Compete For Fkbp126mentioning

confidence: 99%

Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain

Zissimopoulos

Lai

2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The ryanodine receptor-calcium release channel complex (RyR) plays a pivotal role in excitation-contraction coupling in skeletal and cardiac muscle. RyR channel activity is modulated by interaction with FK506-binding protein (FKBP), and disruption of the RyR-FKBP association has been implicated in cardiomyopathy, cardiac hypertrophy, and heart failure. Evidence for an interaction between RyR and FKBP is well documented, both in skeletal muscle (RyR1-FKBP12) and in cardiac muscle (RyR2-FKBP12.6), however definition of the FKBP-binding site remains elusive. Early reports proposed interaction of a short RyR central domain with FKBP12/12.6, however this site has been questioned, and recently an alternative FKBP12.6 interaction site has been identified within the N-terminal half of RyR2. In this study, we report evidence for the human RyR2 C-terminal domain as a novel FKBP12.6-binding site. Using competition binding assays, we find that short C-terminal RyR2 fragments can displace bound FKBP12.6 from the native RyR2, although they are unable to exclusively support interaction with FKBP12.6. 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. We also obtained some evidence for involvement of the RyR2 N-terminal, but not the central domain, in FKBP12.6 interaction. 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.

show abstract

“…While it is striking that the structural differences between two isoforms of a protein arises from just one residue change out of 18, there may be significance for the functional differences between FKBP12 and FKBP12.6. FKBP12 associates with the skeletal ryanodine receptor (RyR1), while FKBP12.6 selectively binds the cardiac ryanodine receptor (RyR2) (Carmody et al, 2001;Gaburjakova et al, 2001;Xin et al, 1999). Ryanodine receptors govern the release of Ca 2+ from the sarcoplasmic reticulum in skeletal and heart muscle, thus triggering muscle contraction (Gaburjakova et al, 2001).…”

Section: Increased Stability Of Mutants Suggests a Tradeoff Betweenmentioning

confidence: 99%

“…FKBP12-FK506/rapamycin complexes inhibit key events in the cytoplasmic signal process, leading to immunosuppression (Schreiber, 1991). FKBP12 and its isoform FKBP12.6 have been found to be crucial regulators of intracellular Ca 2+ release due to their association with ryanodine receptors, thus playing essential roles in excitation-contraction coupling in skeletal and cardiac muscle (Jayaraman et al, 1992;Brillantes et al, 1994;Xin et al, 1999;Carmody et al, 2001;Gaburjakova et al, 2001). Disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy (Xin et al, 2002), while developmental cardiac defects have been reported in FKBP12-deficient mice (Shou et al, 1998).…”

mentioning

confidence: 99%

Energetic and Structural Analysis of the Role of Tryptophan 59 in FKBP12

Fulton¹,

Jackson

Buckle

2003

Biochemistry

View full text Add to dashboard Cite

Tryptophan 59 forms the seat of the hydrophobic ligand-binding site in the small immunophilin FKBP12. Mutating this residue to phenylalanine or leucine stabilizes the protein by 2.72 and 2.35 kcal mol -1 , respectively. Here we report the stability data and 1.7 Å resolution crystal structures of both mutant proteins, complexed with the immunosuppressant rapamycin. Both structures show a relatively large response to mutation involving a helical bulge at the mutation site and the loss of a hydrogen bond that anchors a nearby loop. The increased stability of the mutants is probably due to a combination of improved packing and an entropic gain at the mutation site. The structures are almost identical to that of wild-type FKBP12.6, an isoform of FKBP12 that differs by 18 residues, including Trp59, in its sequence. Therefore, the structural difference between the two isoforms can be attributed almost entirely to the identity of residue 59. It is likely that in FKBP12-ligand complexes Trp59 provides added binding energy at the active site at the expense of protein stability, a characteristic common to other proteins. FKBP12 associates with the ryanodine receptor in skeletal muscle (RyR1), while FKBP12.6 selectively binds the ryanodine receptor in cardiac muscle (RyR2). The structural response to mutation suggests that residue 59 contributes to the specificity of binding between FKBP12 isoforms and ryanodine receptors.

show abstract

FKBP12 associates tightly with the skeletal muscle type 1 ryanodine receptor, but not with other intracellular calcium release channels

Cited by 49 publications

References 41 publications

Calcineurin Localization in Skeletal Muscle Offers Insights into Potential New Targets

Calcineurin Localization in Skeletal Muscle Offers Insights into Potential New Targets

Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain

Energetic and Structural Analysis of the Role of Tryptophan 59 in FKBP12

Contact Info

Product

Resources

About