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Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM.

Woll KA, Haji-Ghassemi O, Van Petegem F
Nat Commun 12 807 (2021)
Related entries: 6w1n, 6x33, 6x34, 6x35, 6x36

Cited: 25 times
EuropePMC logo PMID: 33547325

Abstract

Ryanodine Receptors (RyRs) are massive channels that release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological 'intermediate' conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions.

Articles - 6x32 mentioned but not cited (1)

  1. Pyrrolone Derivatives as Intracellular Allosteric Modulators for Chemokine Receptors: Selective and Dual-Targeting Inhibitors of CC Chemokine Receptors 1 and 2. Ortiz Zacarías NV, van Veldhoven JPD, Portner L, van Spronsen E, Ullo S, Veenhuizen M, van der Velden WJC, Zweemer AJM, Kreekel RM, Oenema K, Lenselink EB, Heitman LH, IJzerman AP. J Med Chem 61 9146-9161 (2018)


Reviews citing this publication (7)

  1. Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation-contraction coupling. Rufenach B, Van Petegem F. J Biol Chem 297 100874 (2021)
  2. Therapeutic potential of pyrrole and pyrrolidine analogs: an update. Jeelan Basha N, Basavarajaiah SM, Shyamsunder K. Mol Divers 26 2915-2937 (2022)
  3. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)
  4. Structural Insight Into Ryanodine Receptor Channelopathies. Hadiatullah H, He Z, Yuchi Z. Front Pharmacol 13 897494 (2022)
  5. Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies. Rossi D, Catallo MR, Pierantozzi E, Sorrentino V. J Gen Physiol 154 e202213115 (2022)
  6. Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases. Iyer KA, Barnakov V, Samsó M. Curr Opin Pharmacol 68 102327 (2023)
  7. Biophysical reviews top five: voltage-dependent charge movement in nerve and muscle. Dulhunty AF. Biophys Rev 15 1903-1907 (2023)

Articles citing this publication (17)

  1. Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment. Miotto MC, Weninger G, Dridi H, Yuan Q, Liu Y, Wronska A, Melville Z, Sittenfeld L, Reiken S, Marks AR. Sci Adv 8 eabo1272 (2022)
  2. Structural and functional interactions between the Ca2+-, ATP-, and caffeine-binding sites of skeletal muscle ryanodine receptor (RyR1). Chirasani VR, Pasek DA, Meissner G. J Biol Chem 297 101040 (2021)
  3. How does flecainide impact RyR2 channel function? Salvage SC, Huang CL, Fraser JA, Dulhunty AF. J Gen Physiol 154 e202213089 (2022)
  4. Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Dulhunty AF. Front Physiol 13 830367 (2022)
  5. Ryanodine receptor 1 (RYR1) mutations in two patients with tubular aggregate myopathy. Vattemi GNA, Rossi D, Galli L, Catallo MR, Pancheri E, Marchetto G, Cisterna B, Malatesta M, Pierantozzi E, Tonin P, Sorrentino V. Eur J Neurosci 56 4214-4223 (2022)
  6. FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease. Richardson SJ, Thekkedam CG, Casarotto MG, Beard NA, Dulhunty AF. Philos Trans R Soc Lond B Biol Sci 378 20220169 (2023)
  7. Molecular mechanism of the severe MH/CCD mutation Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM. Iyer KA, Hu Y, Klose T, Murayama T, Samsó M. Proc Natl Acad Sci U S A 119 e2122140119 (2022)
  8. The Crystal Structure of Calmodulin Bound to the Cardiac Ryanodine Receptor (RyR2) at Residues Phe4246-Val4271 Reveals a Fifth Calcium Binding Site. Yu Q, Anderson DE, Kaur R, Fisher AJ, Ames JB. Biochemistry 60 1088-1096 (2021)
  9. Cryo-EM analysis of scorpion toxin binding to Ryanodine Receptors reveals subconductance that is abolished by PKA phosphorylation. Haji-Ghassemi O, Chen YS, Woll K, Gurrola GB, Valdivia CR, Cai W, Li S, Valdivia HH, Van Petegem F. Sci Adv 9 eadf4936 (2023)
  10. Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms. Gaburjakova J, Gaburjakova M. Int J Mol Sci 24 5409 (2023)
  11. Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations. Kobayashi T, Tsutsumi A, Kurebayashi N, Saito K, Kodama M, Sakurai T, Kikkawa M, Murayama T, Ogawa H. Nat Commun 13 2821 (2022)
  12. Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders. Zhang Y, Rabesahala de Meritens C, Beckmann A, Lai FA, Zissimopoulos S. Front Physiol 13 1032132 (2022)
  13. A bivalent remipede toxin promotes calcium release via ryanodine receptor activation. Maxwell MJ, Thekkedam C, Lamboley C, Chin YK, Crawford T, Smith JJ, Liu J, Jia X, Vetter I, Laver DR, Launikonis BS, Dulhunty A, Undheim EAB, Mobli M. Nat Commun 14 1036 (2023)
  14. Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives. Cholak S, Saville JW, Zhu X, Berezuk AM, Tuttle KS, Haji-Ghassemi O, Alvarado FJ, Van Petegem F, Subramaniam S. Structure 31 790-800.e4 (2023)
  15. Roles and Sources of Calcium in Synaptic Exocytosis. Wang ZW, Riaz S, Niu L. Adv Neurobiol 33 139-170 (2023)
  16. Ryanodine receptor RyR1-mediated elevation of Ca2+ concentration is required for the late stage of myogenic differentiation and fusion. Qiu K, Wang Y, Xu D, He L, Zhang X, Yan E, Wang L, Yin J. J Anim Sci Biotechnol 13 9 (2022)
  17. The RyR1 P3528S Substitution Alters Mouse Skeletal Muscle Contractile Properties and RyR1 Ion Channel Gating. Thekkedam CG, Dutka TL, Van der Poel C, Burgio G, Dulhunty AF. Int J Mol Sci 25 434 (2023)


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