Structural dynamics in the C-terminal domain of calmodulin at low calcium levels 1 1Edited by P. E. Wright

Malmendal, Anders; Evenäs, Johan; Forsén, Sture; Akke, Mikael

doi:10.1006/jmbi.1999.3188

Cited by 151 publications

(236 citation statements)

References 73 publications

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“…This can explain experiments with mutant calmodulin showing that even when two of the calcium-binding sites are ablated, calmodulin can still activate CaMKII to a certain extent (18). It is also consistent with experimental data showing that conformational transitions exist in apo calmodulin (46), and that both apo calmodulin and calmodulin bound to only one calcium ion can exist in open and closed states (47). Finally, calmodulin open structures have been found where only one head was populated by calcium (48).…”

Section: Discussionsupporting

confidence: 85%

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

Stefan

Edelstein

Novère

2008

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

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Calmodulin plays a vital role in mediating bidirectional synaptic plasticity by activating either calcium/calmodulin-dependent protein kinase II (CaMKII) or protein phosphatase 2B (PP2B) at different calcium concentrations. We propose an allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense ( T )] and a high-affinity [relaxed ( R )] state. The four calcium-binding sites are assumed to be nonidentical. The model is consistent with previously reported experimental data for calcium binding to calmodulin. It also accounts for known properties of calmodulin that have been difficult to model so far, including the activity of nonsaturated forms of calmodulin (we predict the existence of open conformations in the absence of calcium), an increase in calcium affinity once calmodulin is bound to a target, and the differential activation of CaMKII and PP2B depending on calcium concentration.

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Section: Discussionsupporting

confidence: 85%

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

Stefan

Edelstein

Novère

2008

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

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“…The 13 C ␣ (i Ϫ 1)͞ 13 C ␣ (i) ⌬R MQ relaxation rates, together with the rates of amide proton exchange with solvent and conformational exchange rates from R 1 experiments, directly pinpoint transient and cooperative unfolding of helix F that involves only a minor population under equilibrium conditions. Importantly, previous results based on 1 4. Location in the structure of residues exhibiting significant correlated conformational exchange contributions to the 13 C ␣ (i Ϫ 1)͞ 13 C ␣ (i) ⌬RMQ rates.…”

Section: Discussionmentioning

confidence: 76%

“…Ligand binding, folding, and enzyme catalysis involve conformational dynamics covering a wide range of time scales and motional amplitudes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). NMR spectroscopy is uniquely suited to study dynamic processes in biomolecules with atomic resolution, on time scales ranging from picoseconds to seconds.…”

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confidence: 99%

Correlated dynamics of consecutive residues reveal transient and cooperative unfolding of secondary structure in proteins

Lundström

Mulder

Akke

2005

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

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Nuclear spin relaxation is a powerful method for studying molecular dynamics at atomic resolution. Recent methods development in biomolecular NMR spectroscopy has enabled detailed investigations of molecular dynamics that are critical for biological function, with prominent examples addressing allostery, enzyme catalysis, and protein folding. Dynamic processes with similar correlation times are often detected in multiple locations of the molecule, raising the question of whether the underlying motions are correlated (corresponding to concerted fluctuations involving many atoms distributed across extended regions of the molecule) or uncorrelated (corresponding to independent fluctuations involving few atoms in localized regions). Here, we have used 13 C ␣ (i ؊ 1)͞ 13 C ␣ (i) differential multiple-quantum spin relaxation to provide direct evidence for correlated dynamics of consecutive amino acid residues in the protein sequence. By monitoring overlapping pairs of residues (i ؊ 1 and i, i and i ؉ 1, etc.), we identified correlated motions that extend through continuous segments of the sequence. We detected significant correlated conformational transitions in the native state of the E140Q mutant of the calmodulin C-terminal domain. Previous work has shown that this domain exchanges between two major conformational states that resemble the functionally relevant open and closed states of the WT protein, with a mean correlation time of Ϸ20 s. The present results reveal that an entire ␣-helix undergoes partial unraveling in a transient and cooperative manner.conformational exchange ͉ NMR ͉ nuclear spin relaxation P rotein dynamics are critical for biological function. Ligand binding, folding, and enzyme catalysis involve conformational dynamics covering a wide range of time scales and motional amplitudes (1-10). NMR spectroscopy is uniquely suited to study dynamic processes in biomolecules with atomic resolution, on time scales ranging from picoseconds to seconds. Chemical or conformational exchange processes that modify the local magnetic environments of nuclear spins on microsecond to millisecond time scales increase the relaxation rates of transverse magnetization (R 2 ), because they introduce a stochastic time dependence of the resonance frequencies. Relaxation dispersion experiments have been developed that quantify conformational exchange contributions to R 2 as a function of the strength of the applied radio-frequency fields, implemented either as CPMG (Carr-Purcell-Meiboom-Gill) pulse trains or continuous-wave spin-locks (8-10). In principle, NMR spectroscopy offers the possibility to monitor conformational exchange processes at every position along the protein backbone and side chains, provided that suitable stable isotopes (e.g., 13 C and 15 N) have been incorporated (4,(11)(12)(13)(14)(15). Importantly, the chemical shifts of different nuclei are sensitive to different types of intramolecular motions, which provides a major motivation for pursuing multinuclear studies of conformational exchange (14-21). Rec...

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“…A similar mechanism in C-terminal CaM domain was also observed from NMR studies, where the Ca 2+ -dependent exchange contribution is dominated by binding loop IV with lower S 2 (higher flexibility) than loop III. 9 Helices B and C and the B/C linker. Fig.…”

Section: Conformational Flexibility and Calcium Bindingmentioning

confidence: 99%

“…5,8 Site specific internal dynamics monitored by model free order parameters S 2 , indicate that the helices of the apo-CaM domains are well-folded on the picosecond to nanosecond timescale, while the Ca 2+ -binding loops, helix-linker and termini are more flexible. 9 On the other hand, spin-spin relaxation (or transverse auto-relaxation) rates, R 2 , indicate that the free and bound forms of the regulatory protein exchange on the millisecond timescale. 10 This two-step Ca 2+ -binding mechanism is based on the hypothesis that Ca 2+ -binding and the resultant conformational change in all two EF-hand domains is determined by a segment of the structure that remains fixed as the domain opens.…”

Section: Introductionmentioning

confidence: 99%

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

Tripathi

Portman

2008

The Journal of Chemical Physics

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Structural dynamics in the C-terminal domain of calmodulin at low calcium levels 1 1Edited by P. E. Wright

Cited by 151 publications

References 73 publications

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

Correlated dynamics of consecutive residues reveal transient and cooperative unfolding of secondary structure in proteins

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

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