Inherent flexibility and protein function: The open/closed conformational transition in the N-terminal domain of calmodulin

Tripathi, Swarnendu; Portman, John J.

doi:10.1063/1.2928634

Cited by 22 publications

(31 citation statements)

References 54 publications

(84 reference statements)

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“…Ca 2+ influences both the inherent flexibility and the conformation of each domain of CaM (SI Appendix, Fig. S9) (43)(44)(45)(46). In our simulations with Ca 2+ , all barrier heights (F1(O-LB), F2(O-LB), F3(O-LB), and F(LB-C)) are decreased (Fig.…”

Section: Resultsmentioning

confidence: 85%

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Liu

Chu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Calmodulin (CaM) is found to have the capability to bind multiple targets. Investigations on the association mechanism of CaM to its targets are crucial for understanding protein-protein binding and recognition. Here, we developed a structure-based model to explore the binding process between CaM and skMLCK binding peptide. We found the cooperation between nonnative electrostatic interaction and nonnative hydrophobic interaction plays an important role in nonspecific recognition between CaM and its target. We also found that the conserved hydrophobic anchors of skMLCK and binding patches of CaM are crucial for the transition from high affinity to high specificity. Furthermore, this association process involves simultaneously both local conformational change of CaM and global conformational changes of the skMLCK binding peptide. We found a landscape with a mixture of the atypical "induced fit," the atypical "conformational selection," and "simultaneously binding-folding," depending on the synchronization of folding and binding. Finally, we extend our discussions on multispecific binding between CaM and its targets. These association characteristics proposed for CaM and skMLCK can provide insights into multispecific binding of CaM. structure-based model | Calmodulin | mixture binding mechanism | multispecific recognition M any biological processes are driven by protein-protein binding. The large-scale domain rearrangements in proteins have long been recognized to have a critical role in biological function. This flexibility or conformational dynamics also provide a new viewpoint of binding. In addition to the "lock-andkey" binding mechanism, proposed by Fischer to describe the rigid binding in enzyme catalysis (1), two scenarios, considering flexibility during binding, emerged and are referred as "induced fit" and "conformational selection," addressing the critical roles of flexibility in protein recognition (2-6).Calmodulin (CaM) is an ubiquitous Ca 2+ binding protein that is involved in a wide range of cellular Ca 2+ -dependent signaling pathways. With incorporating Ca 2+ ions, Ca 2+ -CaM regulates the activity of many kinds of proteins including protein phosphatase, inositol triphosphate kinase, nitric oxide synthase, protein kinases, nicotinamide adenine dinucleotide kinase, Ca 2+ pumps, and proteins involved in motility (7-9). The binary complex Ca 2+ -CaM is found to have the capability to bind over 300 targets (7)(8)(9). Exploring the molecular mechanism of Ca 2+ -CaM binding to the different targets is crucial for understanding protein-protein multispecific recognition. X-ray crystallography experiments have been performed to resolve Ca 2+ -loaded CaM structure (10). However, complexes of CaM with target enzymes are difficult to study by NMR and the crystallization method, due to the spatial resolution in the experiments. Alternatively, short peptide sequences corresponding to CaM-binding domains are often used to explore CaM-target protein interactions and several studies suggest that these CaM-peptide in...

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Section: Resultsmentioning

confidence: 85%

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Liu

Chu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The energy is determined by the two-body interactions between distant residues E({C},{␣}) ϭ ⌺[i,j] ij uij, where uij is the average of the pair potential u(rij) over H0 (42) and ij is the strength of a fully formed contact between residues i and j, given by Miyazawa-Jernigan interaction parameters (44). The sum is restricted to a set of contacts [i,j] determined by pairs of residues in the proximity in each of the metastable conformations (23). Each metastable conformation has a distinct but overlapping set of contacts [i,j]apo, [i,j]holo, and [i,j] is the union of these sets of contacts.…”

Section: Variational Model Of Conformational Transitionsmentioning

confidence: 99%

“…where i apo (␣0) is the monomer density of the ith residue with respect to the apo conformation described by {r i Napo } (23). Similarly, we represent the relative structural similarity to the holo conformation as…”

Section: Conformational Transition Mechanismmentioning

confidence: 99%

Inherent flexibility determines the transition mechanisms of the EF-hands of calmodulin

Tripathi

Portman

2009

Proc. Natl. Acad. Sci. U.S.A.

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We explore how inherent flexibility of a protein molecule influences the mechanism controlling allosteric transitions by using a variational model inspired from work in protein folding. The striking differences in the predicted transition mechanism for the opening of the two domains of calmodulin (CaM) emphasize that inherent flexibility is key to understanding the complex conformational changes that occur in proteins. In particular, the Cterminal domain of CaM (cCaM), which is inherently less flexible than its N-terminal domain (nCaM), reveals ''cracking'' or local partial unfolding during the open/closed transition. This result is in harmony with the picture that cracking relieves local stresses caused by conformational deformations of a sufficiently rigid protein. We also compare the conformational transition in a recently studied even-odd paired fragment of CaM. Our results rationalize the different relative binding affinities of the EF-hands in the engineered fragment compared with the intact odd-even paired EF-hands (nCaM and cCaM) in terms of changes in flexibility along the transition route. Aside from elucidating general theoretical ideas about the cracking mechanism, these studies also emphasize how the remarkable intrinsic plasticity of CaM underlies conformational dynamics essential for its diverse functions.T o understand protein function, it is often essential to characterize large conformational changes that occur upon ligand binding. Within the population shift mechanism of allosteric conformational change (1), the bound complex is formed when a ligand selects and stabilizes a weakly populated conformational ensemble from the kinetically accessible states of the unbound folded protein. Such conformational dynamics imply an inherent flexibility or ''intrinsic plasticity'' of the folded state. In this article, we focus on how this inherent flexibility of a protein molecule influences the mechanism controlling the kinetics of allosteric transitions. There are a couple of possible scenarios for the transition mechanism in terms of changes in conformational flexibility. One possibility is that the flexibility adjusts smoothly to conformational deformations connecting two specific metastable states in the free-energy surface. In this case, the inherent flexibility of the protein remains relatively constant if the metastable states have similar flexibilities or else changes smoothly between the flexibilities of the metastable states if the flexibilities are different. An alternative mechanism, called ''cracking'' (2), has recently been proposed. In terms of conformational f lexibility, cracking involves nonmonotonic changes in flexibility along the transitions route. In particular, the flexibility of specific regions of the protein may transiently increase through local unfolding. As explained in ref. 2, local unfolding can relieve specific areas of high stress during conformational deformations that would result in high free-energy barriers if the protein remained uniformly folded throughout the transi...

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“…Fig. 4 reports details for a typical accepted event during a closing simulation of the open Calmodulin NT model, which undergoes transformation in its binding loops when deprived of its calcium ions [37,38]. For this simulation, we defined as pivots residues 18 to 31, which includes the first binding loop, and residues 54 to 67, which includes the second binding loop.…”

Section: Interactionmentioning

confidence: 99%

Holographic multiscale method used with non-biased atomistic forcefields for simulation of large transformations in protein

Dupuis

Mousseau

2012

J. Phys.: Conf. Ser.

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Abstract.We present a multiscale approach for simulating protein flexibility. The originality of our method is its ability to perform dynamic multiscaling based on continuous revaluation of overlapping areas. The holographic multiscale method overcomes the limitations of motions determined by predefined and fixed high-level descriptions and allows the reproduction of residue-specific impact on large scale motion. The method is tested with two different nonbiased all atom implicit solvent forcefields. These show stretched proteins A and G, with maintained secondary structure, folding back near native states in a small number of transition events, demonstrating the advantages of this multiscale approach.

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Inherent flexibility and protein function: The open/closed conformational transition in the N-terminal domain of calmodulin

Abstract: The key to understanding a protein's function often lies in its conformational dynamics. We de-

Cited by 22 publications

References 54 publications

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Inherent flexibility determines the transition mechanisms of the EF-hands of calmodulin

Holographic multiscale method used with non-biased atomistic forcefields for simulation of large transformations in protein

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