A guide to the 3D structure of the ryanodine receptor type 1 by cryoEM

Samsó, Montserrat

doi:10.1002/pro.3052

Cited by 35 publications

(45 citation statements)

References 138 publications

(247 reference statements)

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“…Critical for Ca 2+ flow0.710.53058+IVCT[50, 63, 89] 46:33p.Gly2434ArgCS (Bsol)MH/CCD hotspot 2, NTD-Bsol contact (DP4 peptide)0.091.5121125+IVCT ↑, ryanodine binding and ↑ sensitivity to caffeine and 4C m C[13, 18, 49, 58]p.Met4875ValCAC (Pore)MH/CCD hotspot 3, luminal triadin binding, retention of RyR-CSQ proximity and ability for rapid Ca 2+ release0.00.22121None[37, 38, 89]Pore-TMx interface 47:34p.Gly1165GlyCS (SPRY2)Residue close to RyR1-Cav1.1 interaction siten/an/an/an/aNone[64]p.Arg1606HisCS (SPRY3)Probable RyR1-Cav1.1 interaction0.070.12829None[64]SPRY3-RY1&2 interfacep.Glu4167* a CAC (Csol)MH/CCD hotspot 3n/an/an/an/aNone[89] CS CS, CSQ calsequestrin, CAC CAC, MH malignant hyperthermia, CCD central core disease, Bsol bridging solenoid, NTD-B N-terminal domain B, NTD-A N-terminal domain A, SPRY1 SP1a/ryanodine receptor domain 1, Nsol N-terminal solenoid, RY1&2 RYR repeats 1 and 2, SPRY3 SP1a/ryanodine receptor domain 3, Pore chan...…”

Section: Resultsmentioning

confidence: 99%

“…In cases with variants that affected only the CAC, the pore region inclusive of the helical-bundle between S2 and S3 (S2S3), was affected most often (76% of cases). In three related cases (39, 40, 41) with a rhabdomyolysis clinical phenotype, the same RYR1 variant (p.Asp4505His) affected a currently unresolved region between amino acid residues 4354–4631 [64]. In cases with variants that affected both RyR1 domains, Bsol within the CS was the most frequently affected region (84% of cases).…”

Section: Resultsmentioning

confidence: 99%

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Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.Electronic supplementary materialThe online version of this article (10.1007/s00415-018-9033-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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“…Recently published cryo-EM structures of RyR1 in multiple functional states have identified the binding sites for the channel activators Ca 2+ , CFF, and ATP at inter-domain interfaces of the Cterminal domain (8,(13)(14)(15)(16)(17)(18)30). Precisely, Ca 2+ binding site is identified in the large cytoplasmic domain of RyR1, ATP-binding site is located close to pore region at the interface of two chains, and CFF binding pocket is located in relatively close proximity (~20 Å) to Ca 2+ binding site.…”

Section: Resultsmentioning

confidence: 99%

“…Many channel endogenous modulators control RyR1 such as Ca 2+ , ATP, Mg 2+ and calmodulin and exogenous effectors such as caffeine (CFF) and ryanodine (3). The binding sites of several RyR modulators are within 200 Å from the pore region in RyRs (8), which denotes the significance of allosteric communications within the channels. Some previous studies suggest the possibility of allosteric regulation; however, the mechanisms remain to be unraveled.…”

Section: Introductionmentioning

confidence: 99%

“…Recent advances in single-particle cryo-electron microscopy (cryo-EM) have captured RyR1 in multiple functional states and provided insights on RyR1 regulation by key activators Ca 2+ , ATP and CFF (8,(13)(14)(15)(16)(17)(18). Particularly, the high resolution cryo-EM structures solved by Des Georges et al (17) emphasized that the binding of Ca 2+ , ATP, and CFF can trigger local and global structural changes in RyR1 to induce channel opening.…”

Section: Introductionmentioning

confidence: 99%

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Mapping Co-regulation Pathways among Ligand Binding sites in RyR1

Chirasani

Popov

Meissner

et al. 2019

Preprint

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Ryanodine receptor 1 (RyR1) is an intracellular calcium (Ca 2+ ) release channel required for skeletal muscle contraction. RyR1 is co-regulated by multiple activators -Ca 2+ , ATP and caffeine (CFF), yet the mechanism of co-regulation and the action synergy of these activators is unknown. Here, we report the detailed network of allosteric connections between the three ligand sites and the pore region in (i) Ca 2+ boundclosed, (ii) ATP/CFF boundclosed, (iii) Ca 2+ /ATP/CFF boundclosed and (iv) Ca 2+ /ATP/CFF boundopen RyR1 states. We find that two dominant paths mediate the communication between the Ca 2+ binding site and pore region in Ca 2+ -only state. ATP/CFF-only occupiedclosed RyR1 has two additional paths with CFF-but not ATP-occupied path using part of the closed Ca 2+ -only pathway. In the presence of Ca 2+ , ATP and CFF, major differences between the open and closed states are identified with both using part of the paths of the closed Ca 2+ -only and ATP/CFF-only states. We find that the three activators Ca 2+ , ATP, and CFF propagate their effects to the pore region through a network of partially overlapping pathways. Such coordination of allosteric pathway underlies the molecular basis of synergy of channel regulation by multiple activators. Statement of SignificanceRyRs are a group of Ca 2+ channels that bind to several endogenous modulators and regulate Ca 2+ release through closed-to-open gating transition. Despite the high-resolution structural data available for RyR1, the allosteric mechanism of RyR1 gating remains elusive. In this study, we employed graph-theoretical approach to demonstrate the allosteric network of synergistic interaction among various activators in RyR1. To our knowledge, for the first time we were able to identify the co-regulation among ligand sites in RyR1 to regulate the closed-to-open gating transition. The explored allosteric coupling in RyR1 may assist in designing advanced therapeutics for several debilitating diseases. Our findings in this study will assist to design new strategies for controlled allosteric regulation of RyR1 functionality in future.

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Mapping co‐regulatory interactions among ligand‐binding sites in ryanodine receptor 1

et al. 2021

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Ryanodine receptor 1 (RyR1) is an intracellular calcium ion (Ca 2+ ) release channel required for skeletal muscle contraction. Although cryo-electron microscopy identified binding sites of three coactivators Ca 2+ , ATP, and caffeine (CFF), the mechanism of co-regulation and synergy of these activators is unknown. Here, we report allosteric connections among the three ligand-binding sites and pore region in (i) Ca 2+ bound-closed, (ii) ATP/CFF bound-closed, (iii) Ca 2+ /ATP/CFF bound-closed, and (iv) Ca 2+ /ATP/CFF bound-open RyR1 states. We identified two dominant networks of interactions that mediate communication between the Ca 2+ -binding site and pore region in Ca 2+ bound-closed state, which partially overlapped with the pore communications in ATP/CFF bound-closed RyR1 state. In Ca 2+ /ATP/CFF bound-closed and -open RyR1 states, co-regulatory interactions were analogous to communications in the Ca 2+ bound-closed and ATP/CFF bound-closed states. Both ATP-and CFFbinding sites mediate communication between the Ca 2+ -binding site and the pore region in Ca 2+ /ATP/CFF bound-open RyR1 structure. We conclude that Ca 2+ , ATP, and CFF propagate their effects to the pore region through a network of overlapping interactions that mediate allosteric control and molecular synergy in channel regulation.

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A guide to the 3D structure of the ryanodine receptor type 1 by cryoEM

Cited by 35 publications

References 138 publications

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Mapping Co-regulation Pathways among Ligand Binding sites in RyR1

Mapping co‐regulatory interactions among ligand‐binding sites in ryanodine receptor 1

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