3qr5

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Structure of the first domain of a cardiac Ryanodine Receptor mutant with exon 3 deleted

Structural highlights

3qr5 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RYR2_MOUSE Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.[1] [2] [3] [4]

Publication Abstract from PubMed

Mutations in the cardiac Ryanodine Receptor (RYR2) are linked to triggered arrhythmias. Removal of exon 3 results in a severe form of catecholaminergic polymorphic ventricular tachycardia (CPVT). This exon encodes secondary structure elements that are crucial for folding of the N-terminal domain (NTD), raising the question of why the deletion is neither lethal nor confers a loss of function. We determined the 2.3 A crystal structure of the NTD lacking exon 3. The removal causes a structural rescue whereby a flexible loop inserts itself into the beta trefoil domain and increases thermal stability. The exon 3 deletion is not tolerated in the corresponding RYR1 domain. The rescue shows a novel mechanism by which RYR2 channels can adjust their Ca(2)(+) release properties through altering the structure of the NTD. Despite the rescue, the deletion affects interfaces with other RYR2 domains. We propose that relative movement of the NTD is allosterically coupled to the pore region.

The deletion of exon 3 in the cardiac ryanodine receptor is rescued by beta strand switching.,Lobo PA, Kimlicka L, Tung CC, Van Petegem F Structure. 2011 Jun 8;19(6):790-8. doi: 10.1016/j.str.2011.03.016. PMID:21645850[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
7 reviews cite this structure
Ryanodine receptors: structure and function.
Van et al. (2012)
6 more
32 other articles
No citations found

See Also

References

  1. ↑ Zhao M, Li P, Li X, Zhang L, Winkfein RJ, Chen SR. Molecular identification of the ryanodine receptor pore-forming segment. J Biol Chem. 1999 Sep 10;274(37):25971-4. PMID:10473538
  2. ↑ Takeshima H, Komazaki S, Hirose K, Nishi M, Noda T, Iino M. Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2. EMBO J. 1998 Jun 15;17(12):3309-16. PMID:9628868 doi:10.1093/emboj/17.12.3309
  3. ↑ van Oort RJ, McCauley MD, Dixit SS, Pereira L, Yang Y, Respress JL, Wang Q, De Almeida AC, Skapura DG, Anderson ME, Bers DM, Wehrens XH. Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation. 2010 Dec 21;122(25):2669-79. doi: 10.1161/CIRCULATIONAHA.110.982298., Epub 2010 Nov 15. PMID:21098440 doi:10.1161/CIRCULATIONAHA.110.982298
  4. ↑ Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, Fruen BR, Bers DM. Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks. Circ Res. 2010 Jun 11;106(11):1743-52. doi: 10.1161/CIRCRESAHA.110.219816. Epub, 2010 Apr 29. PMID:20431056 doi:10.1161/CIRCRESAHA.110.219816
  5. ↑ Lobo PA, Kimlicka L, Tung CC, Van Petegem F. The deletion of exon 3 in the cardiac ryanodine receptor is rescued by β strand switching. Structure. 2011 Jun 8;19(6):790-8. PMID:21645850 doi:10.1016/j.str.2011.03.016

Contents


PDB ID 3qr5

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