Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21817 (RyR1)
 1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 12-kDa immunophilin (FKBP12) is an integral component of the skeletal muscle ryanodine receptor (RyR). The RyR is a hetero-oligomeric complex with structural formula (FKBP)4(Ryr1)4, where Ryr1 is the 565-kDa product of the Ryr1 gene. To aid in the detection of the immunophilin's location in the receptor, we exchanged the FKBP12 present in RyR-enriched vesicles derived from sarcoplasmic reticulum with an engineered construct of FKBP12 fused to glutathione S-transferase and then isolated the complexes. Cryoelectron microscopy and image averaging of the complexes (in an orientation displaying the RyR's fourfold symmetry) revealed four symmetrically distributed, diffuse density regions that were located just outside the boundary defining the cytoplasmic assembly of the RyR. These regions are attributed to the glutathione transferase portion of the fusion protein because they are absent from receptors lacking the fusion protein. To more precisely define the location of FKBP12, we similarly analyzed complexes of RyR containing FKBP12 itself. Apparently some FKBP is lost during the purification or storage of the RyR because, to detect the receptor-bound immunophilin, it was necessary to add FKBP12 to the purified receptor before electron microscopy. Averaged images of these complexes showed a region of density that had not been observed previously in images of isolated receptors, and its position, along the edges of the transmembrane assembly, agreed with the position of the FKBP12 deduced from the experiments with the fusion protein. The proposed locations for FKBP12 are about 10 nm from the transmembrane baseplate assembly that contains the ion channel of the RyR.
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PMID:Cryoelectron microscopy resolves FK506-binding protein sites on the skeletal muscle ryanodine receptor. 878 29

The immunophilin, FK506-binding protein (FKBP12), is an essential component of the ryanodine receptor channel complex of skeletal muscle (RyR1) and modulates intracellular calcium signaling from the endoplasmic reticulum. The cardiac muscle RyR isoform (RyR2) specifically associates with a distinct FKBP isoform, FKBP12.6. Previous studies have led to the proposal that the central domain of RyR1 exclusively mediates the interaction with FKBP12. To characterize the topography of the FKBP12.6 binding site on the human cardiac RyR2, we have applied complementary protein-protein interaction methods using both in vivoyeast two-hybrid analysis and in vitroimmunoprecipitation experiments. Our results indicate an absence of interaction of FKBP12/12.6 with fragments containing the central domain of either RyR1, RyR2, or RyR3. Furthermore, no interaction was detected between FKBP12.6 with a series of overlapping fragments encompassing the entire RyR2, either individually or in multiple combination. We also found that a distinct, alternatively spliced variant of FKBP12.6 was unable to interact with RyR. In contrast, we successfully demonstrated a robust association between the cytoplasmic domain of transforming growth factor-beta receptor type I and both FKBP12 and FKBP12.6 in parallel positive control experiments, as well as between native RyR2 and FKBP12.6. These results suggest that the specific interaction of FKBP12.6 with RyR2, and generally of FKBPs with any RyR isoform, is not readily reconstituted by peptide fragments corresponding to central RyR domains. Further structural analysis will be necessary to unravel this intricate signaling system and the current model of FKBP12-RyR interaction via a single, central RyR epitope may therefore require revision.
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PMID:Central domain of the human cardiac muscle ryanodine receptor does not mediate interaction with FKBP12.6. 1604 46

Strength deficits associated with eccentric contraction-induced muscle injury stem, in part, from impaired voltage-gated sarcoplasmic reticulum (SR) Ca(2+) release. FKBP12 is a 12-kD immunophilin known to bind to the SR Ca(2+) release channel (ryanodine receptor, RyR1) and plays an important role in excitation-contraction coupling. To assess the effects of eccentric contractions on FKBP12 content, we measured anterior crural muscle (tibialis anterior [TA], extensor digitorum longus [EDL], extensor hallucis longus muscles) strength and FKBP12 content in pellet and supernatant fractions after centrifugation via immunoblotting from mice before and after a single bout of either 150 eccentric or concentric contractions. There were no changes in peak isometric torque or FKBP12 content in TA muscles after concentric contractions. However, FKBP12 content was reduced in the pelleted fraction immediately after eccentric contractions, and increased in the soluble protein fraction 3 day after injury induction. FKBP12 content was correlated (P = 0.025; R(2) = 0.38) to strength deficits immediately after injury induction. In summary, eccentric contraction-induced muscle injury is associated with significant alterations in FKBP12 content after injury, and is correlated with changes in peak isometric torque.
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PMID:Eccentric contractions disrupt FKBP12 content in mouse skeletal muscle. 2534 64