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TitleA cryo-EM-based model of phosphorylation- and FKBP12.6-mediated allosterism of the cardiac ryanodine receptor.
Journal, issue, pagesSci Signal, Vol. 10, Issue 480, Year 2017
Publish dateMay 23, 2017
AuthorsSonali Dhindwal / Joshua Lobo / Vanessa Cabra / Demetrio J Santiago / Ashok R Nayak / Kelly Dryden / Montserrat Samsó /
PubMed AbstractType 2 ryanodine receptors (RyR2s) are calcium channels that play a vital role in triggering cardiac muscle contraction by releasing calcium from the sarcoplasmic reticulum into the cytoplasm. ...Type 2 ryanodine receptors (RyR2s) are calcium channels that play a vital role in triggering cardiac muscle contraction by releasing calcium from the sarcoplasmic reticulum into the cytoplasm. Several cardiomyopathies are associated with the abnormal functioning of RyR2. We determined the three-dimensional structure of rabbit RyR2 in complex with the regulatory protein FKBP12.6 in the closed state at 11.8 Å resolution using cryo-electron microscopy and built an atomic model of RyR2. The heterogeneity in the data set revealed two RyR2 conformations that we proposed to be related to the extent of phosphorylation of the P2 domain. Because the more flexible conformation may correspond to RyR2 with a phosphorylated P2 domain, we suggest that phosphorylation may set RyR2 in a conformation that needs less energy to transition to the open state. Comparison of RyR2 from cardiac muscle and RyR1 from skeletal muscle showed substantial structural differences between the two, especially in the helical domain 2 (HD2) structure forming the Clamp domain, which participates in quaternary interactions with the dihydropyridine receptor and neighboring RyRs in RyR1 but not in RyR2. Rigidity of the HD2 domain of RyR2 was enhanced by binding of FKBP12.6, a ligand that stabilizes RyR2 in the closed state. These results help to decipher the molecular basis of the different mechanisms of activation and oligomerization of the RyR isoforms and could be extended to RyR complexes in other tissues.
External linksSci Signal / PubMed:28536302
MethodsEM (single particle)
Resolution11.0 Å
Structure data

EMDB-8303, PDB-5l1d:
Structure of rabbit RyR2 in complex with FKBP12.6 in a closed state (conformation C1)
Method: EM (single particle) / Resolution: 11.0 Å

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN/ISOMERASE / Calcium Release Channel / Ryanodine Receptor / TRANSPORT PROTEIN-ISOMERASE complex

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