Role of Calcium in Modulating the Conformational Landscape and Peptide Binding Induced Closing of Calmodulin

Ghosh, Catherine; Jana, Biman

doi:10.1021/acs.jpcb.1c00783

Cited by 10 publications

(9 citation statements)

References 69 publications

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“…While the transition path is continuous, we set the ΔRMSD to 0.5 Å to save frames, as this spacing is commonly used in biased sampling when using RMSD as a CV. 37 We have repeated the NMA analysis and show in Figure S2 that transition paths are highly overlapped in these replicas, suggesting that the NMA results are convergent. Notably, we did not compare frames from different paths (with approximately the same frame number) for "superiority" because these intermediate structures are naturally high energy conformations compared to the end states (energy minima).…”

Section: Transition Pathwaymentioning

confidence: 84%

Synergistic Binding of ATP and Nucleic Acids Necessitates UPF1’s ATPase Functional Cycle

Sun

Liu

Zhang

et al. 2023

J. Chem. Inf. Model.

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UPF1 is a core protein in the nonsense mRNA degradation (NMD) surveillance pathway that degrades aberrant mRNA. UPF1 has both ATPase and RNA helicase activities, but it exhibits mutually exclusive binding of ATP and RNA. This suggests intricate allosteric coupling between ATP and RNA binding that remains unresolved. In this study, we used molecular dynamics simulations and dynamic network analyses to probe the dynamics and free energy landscapes covering UPF1 crystal structures resolved in the Apo state, the ATP bound state, and the ATP-RNA bound (catalytic transition) state. Free energy calculations show that in the presence of ATP and RNA, the transition from the Apo state to the ATP bound state is an uphill process but becomes a downhill process when transitioning to the catalytic transition state. Allostery potential analyses reveal that the Apo and catalytic transition states are mutually allosterically activated toward each other, reflecting the intrinsic ATPase function of UPF1. The Apo state is also allosterically activated toward the ATP bound state. However, binding ATP alone leads to an allosterically trapped state that is difficult to revert to either the Apo or the catalytic transition state. The high allostery potential of Apo UPF1 toward different states results in a “first come, first served” mechanism that requires the synergistic binding of ATP and RNA to drive the ATPase cycle. Our results reconcile UPF1’s ATPase and RNA helicase activities within an allostery framework and may apply to other SF1 helicases, as we demonstrate that UPF1’s allostery signaling pathways prefer the RecA1 domain over the equally fold-conserved RecA2 domain, and this preference coincides with higher sequence conservation in the RecA1 domain across typical human SF1 helicases.

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Section: Transition Pathwaymentioning

confidence: 84%

Synergistic Binding of ATP and Nucleic Acids Necessitates UPF1’s ATPase Functional Cycle

Sun

Liu

Zhang

et al. 2023

J. Chem. Inf. Model.

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“…This has led to the view that globular proteins have only one native state and that the biological function of proteins is tied to this unique native structure. New biophysical and computational techniques have revealed several departures from the “one sequence, one structure, one function” canon by demonstrating the contribution of structural plasticity to biological functions. − This necessitated the inclusion of conformational flexibility and internal dynamics in the description of the native state. New categories such as intrinsically disordered proteins, chameleonic sequences, morpheeins, and metamorphic proteins have further diversified the protein universe …”

Section: Introductionmentioning

confidence: 99%

Curious Case of MAD2 Protein: Diverse Folding Intermediates Leading to Alternate Native States

Ghosh

Jana

2022

J. Phys. Chem. B

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Anfinsen's dogma postulates that for one sequence there will be only one unique structure that is necessary for the functioning of the protein. However, over the years there have been a number of departures from this postulate. As far as function is considered, there are growing examples of proteins that "moonlight", perform multiple unrelated functions. With the discovery of intrinsically disordered proteins, morpheeins, chameleonic sequences, and metamorphic proteins that can switch folds, we have acquired a more nuanced understanding of protein folding and dynamics. Appearing to apparently contradict the classical folding paradigm, metamorphic proteins are considered exotic species. In this work, we have explored the free energy landscape and folding pathways of the metamorphic protein MAD2 which is an important component of the spindle checkpoint. It coexists in two alternate states: the inactive open state and the active closed state. Using a dual-basin structure-based model approach we have shown that a variety of intermediates and multiple pathways are available to MAD2 to fold into its alternate forms. This approach involves performing molecular dynamics simulations of coarse-grained models of MAD2 where the structural information regarding both of its native conformations is explicitly included in terms of their native contacts in the force field used. Detailed analyses have indicated that some of the contacts within the protein play a key role in determining which folding pathway will be selected and point to a probable long-range communication between the N and the C termini of the protein that seems to control its folding. Finally, our work also provides a rationale for the experimentally observed preference of the ΔC 10 variant of MAD2 to exist in the open state.

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“…Considerable efforts have attempted to decipher the molecular bases of the aforementioned observables. Computations and NMR experiments have revealed the contributions of certain residues in CaM’s linker to allow target-free CaM to sample conformations specific to the target-bound CaM state. , Asidefrom the binding mode, changing the linker’s flexibility shifts CaM’s conformational equilibrium between extended and compact forms, which eventually alters the binding kinetics between CaM and its target . Using synthetic linkers and NMR techniques, it has been shown that the extent of interdomain associations is maximized as the linker length and rigidity approach that of the wild-type linker .…”

Section: Introductionmentioning

confidence: 99%

Calmodulin’s Interdomain Linker Is Optimized for Dynamics Signal Transmission and Calcium Binding

Sun

Kekenes‐Huskey

2022

J. Chem. Inf. Model.

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Linkers are ubiquitous in multidomain proteins. These linkers are integral to protein functions, and accumulating evidence suggests that the linkers’ versatile roles are encoded in their sequences. However, a molecular picture of how amino acid differences in the linker influence protein function is still lacking. By using extensive Gaussian-accelerated MD coupled with dynamic network analysis, we reveal the molecular bases underlying the linker’s role in Calmodulin (CaM), a highly conserved Ca2+-signaling hub in eukaryotes. Three CaM constructs comprising a wild-type linker, a flexible linker (four glycines at position D78-S81), and a rigid linker (four prolines at position D78-S81) were simulated. We show that the flexible linker resembles the wild type in allowing CaM to sample a large ensemble of conformations while the rigid linker confines the sampling. Our simulations recapture experimental observations that target binding enhances the Ca2+ affinity to CaM’s EF-hand sites at the N-domain. However, only the wild-type linker can both correctly capture the Ca2+ binding order and maintain the α-helical structure of the domain. The other two constructs either bind Ca2+ in an incorrect order or exhibit unfolding of an N-domain helix. We demonstrate that the wild-type linker achieves these outcomes by transmitting interdomain dynamics efficiently. This was evidenced by stronger (anti)correlations among the linker residues, decoupling of the hydrogen bonds between A1–A15 and V35–E45, and structuring of the N-domain for Ca2+ binding. This decoupling was not evident for the other two constructs. Lastly, we show that the wild-type linker’s optimal transmission stems from its thermodynamically favorable strain and solvation relative to the other two constructs. Our results show how the linker sequence tunes CaM function, suggesting possible mechanisms for changes in linker properties such as mutations or post-translational modifications to modulate protein/substrate binding.

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Role of Calcium in Modulating the Conformational Landscape and Peptide Binding Induced Closing of Calmodulin

Cited by 10 publications

References 69 publications

Synergistic Binding of ATP and Nucleic Acids Necessitates UPF1’s ATPase Functional Cycle

Synergistic Binding of ATP and Nucleic Acids Necessitates UPF1’s ATPase Functional Cycle

Curious Case of MAD2 Protein: Diverse Folding Intermediates Leading to Alternate Native States

Calmodulin’s Interdomain Linker Is Optimized for Dynamics Signal Transmission and Calcium Binding

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