The FKBP12 subunit modifies the long-range allosterism of the ryanodine receptor
| Autor: | Montserrat Samsó, Tyler W.E. Steele |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
RYR1
0303 health sciences Ryanodine receptor Chemistry Protein subunit 030302 biochemistry & molecular biology Cryoelectron Microscopy Context (language use) Ryanodine Receptor Calcium Release Channel Tacrolimus Binding Protein 1A musculoskeletal system Article 03 medical and health sciences FKBP Tetramer Structural Biology Cytoplasm Biophysics Animals Humans tissues Intracellular 030304 developmental biology Protein Binding |
| Popis: | Ryanodine receptors (RyRs) are large conductance intracellular channels controlling intracellular calcium homeostasis in myocytes, neurons, and other cell types. Loss of RyR’s constitutive cytoplasmic partner FKBP results in channel sensitization, dominant subconductance states, and increased cytoplasmic Ca2+. FKBP12 binds to RyR1’s cytoplasmic assembly 130 A away from the ion gate at four equivalent sites in the RyR1 tetramer. To understand how FKBP12 binding alters RyR1’s channel properties, we studied the 3D structure of RyR1 alone in the closed conformation in the context of the open and closed conformations of FKBP12-bound RyR1. We analyzed the metrics of conformational changes of existing structures, the structure of the ion gate, and carried out multivariate statistical analysis of thousands of individual cryoEM RyR1 particles. We find that under closed state conditions, in the presence of FKBP12, the cytoplasmic domain of RyR1 adopts an upward conformation, whereas absence of FKBP12 results in a relaxed conformation, while the ion gate remains closed. The relaxed conformation is intermediate between the RyR1-FKBP12 complex closed (upward) and open (downward) conformations. The closed-relaxed conformation of RyR1 appears to be consistent with a lower energy barrier separating the closed and open states of RyR1-FKBP12, and suggests that FKBP12 plays an important role by restricting conformations within RyR1’s conformational landscape. |
| Databáze: | OpenAIRE |
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