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Forces and energetics of the canonical tetrameric cation channel gating.

ABSTRACT: The canonical gating mechanism of tetrameric cation channels involves the spreading of the pore-lining helices at the so-called bundle-crossing gate. Despite a wealth of structural information, we lack a physical description of the gating process. Here, I took advantage of an entropic polymer stretching physical model and MthK structures to derive the forces and energies involved in pore-domain gating. In MthK, the Ca²⁺-induced conformational change in the RCK domain alone opens the bundle-crossing gate through pulling via unfolded linkers. In the open conformation, the linkers serve as entropic springs between the RCK domain and bundle-crossing gate that store an elastic potential energy of 3.6k_BT and exert 9.8 pN (piconewton) radial pulling force to keep the gate open. I further derive that the work to load the linkers to prime the channel for opening is up to 3.8k_BT, exerting up to 15.5 pN to pull the bundle-crossing open. Opening of the bundle-crossing leads to a release of 3.3k_BT spring potential energy. Thus, the closed/RCK-apo and the open/RCK-Ca²⁺ conformations are separated by a barrier of several k_BT. I discuss how these findings relate to the functional properties of MthK and suggest that given the architectural conservation of the helix-pore-loop-helix pore-domain among all tetrameric cation channels, these physical parameters might be quite general.

SUBMITTER: Scheuring S

PROVIDER: S-EPMC10334803 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Forces and energetics of the canonical tetrameric cation channel gating.

Scheuring Simon S

Proceedings of the National Academy of Sciences of the United States of America 20230703 28

The canonical gating mechanism of tetrameric cation channels involves the spreading of the pore-lining helices at the so-called bundle-crossing gate. Despite a wealth of structural information, we lack a physical description of the gating process. Here, I took advantage of an entropic polymer stretching physical model and MthK structures to derive the forces and energies involved in pore-domain gating. In MthK, the Ca<sup>2+</sup>-induced conformational change in the RCK domain alone opens the b ...[more]

PMID: 37399394

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Project description:Despite its importance and abundance of experimental data, the molecular mechanism of RyR2 activation by calcium is poorly understood. Recent experimental studies involving coexpression of wild-type (WT) RyR2 together with a RyR2 mutant deficient in calcium-dependent activation (Li, P., and S.R. Chen. 2001. J. Gen. Physiol. 118:33-44) revealed large variations of calcium sensitivity of the RyR tetramers with their monomer composition. Together with previous results on kinetics of Ca activation (Zahradníková, A., I. Zahradník, I. Györke, and S. Györke. 1999. J. Gen. Physiol. 114:787-798), these data represent benchmarks for construction and testing of RyR models that would reproduce RyR behavior and be structurally realistic as well. Here we present a theoretical study of the effects of RyR monomer substitution by a calcium-insensitive mutant on the calcium dependence of RyR activation. Three published models of tetrameric RyR channels were used either directly or after adaptation to provide allosteric regulation. Additionally, two alternative RyR models with Ca binding sites created jointly by the monomers were developed. The models were modified for description of channels composed of WT and mutant monomers. The parameters of the models were optimized to provide the best approximation of published experimental data. For reproducing the observed calcium dependence of RyR tetramers containing mutant monomers (a) single, independent Ca binding sites on each monomer were preferable to shared binding sites; (b) allosteric models were preferable to linear models; (c) in the WT channel, probability of opening to states containing a Ca2+-free monomer had to be extremely low; and (d) models with fully Ca-bound closed states, additional to those of an Monod-Wyman-Changeaux model, were preferable to models without such states. These results provide support for the concept that RyR activation is possible (albeit vanishingly small in WT channels) in the absence of Ca2+ binding. They also suggest further avenues toward understanding RyR gating.

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Forces and energetics of the canonical tetrameric cation channel gating.

Publications

Forces and energetics of the canonical tetrameric cation channel gating.

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