A Closed Compact Structure of Native Ca2+-Calmodulin

Fallon, Jennifer L.; Quiocho, Florante A.

doi:10.1016/j.str.2003.09.004

Cited by 161 publications

(220 citation statements)

References 23 publications

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“…4b). (It is in fact close to that recently described as a contracted-open conformation 26 ). The target helix thus is found in a much less buried position within this lobe than in a classic open lobe (Fig.…”

Section: Insert-2 Constitutes a Novel Calmodulin Binding Motifsupporting

confidence: 90%

The structure of the myosin VI motor reveals the mechanism of directionality reversal

Menetrey

Bahloul

Wells

et al. 2005

Nature

205

234

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We have solved a 2.4Å structure of a truncated version of the reverse direction myosin motor, myosin VI, that contains the motor domain and binding sites for two calmodulins. The structure reveals only minor differences in the motor domain as compared to plus-end directed myosins, with the exception of two unique inserts. The first insert is near the nucleotide-binding pocket, and alters the rates of nucleotide association and dissociation. The second unique insert forms an integral part of the myosin VI converter domain along with a calmodulin bound to a previously unseen binding motif within the insert. This serves to redirect the effective "lever arm" of myosin VI, which includes a second calmodulin bound to an "IQ motif," towards the pointed (−) end of the actin filament. This repositioning largely accounts for the reverse directionality of this class of myosin motors. We propose a model incorporating a kinesin-like uncoupling/docking mechanism to fully explain the movements of myosin VI.The myosin superfamily is composed of eighteen classes of molecular motor proteins, the vast majority of which traffic toward the barbed (+) end of actin filaments 1 . Class VI myosins were the first of the superfamily identified to traffic toward the pointed (−) end of the actin filament 2 . They function in a number of critical intracellular processes such as vesicular membrane traffic, cell migration, maintenance of stereocilia and mitosis [3][4][5][6] .The current view of how myosin motors couple ATP hydrolysis and actin binding to movement is known as the lever arm hypothesis 7 . In essence the proposed mechanism is that nucleotide binding, hydrolysis and product release are all coupled to small movements within the myosin motor core. These movements are amplified and transmitted via a region that has been termed the "converter" domain to a lever arm consisting of a target helix and associated light chains/ calmodulins. The lever arm further amplifies the motions of the converter domain into large directed movements. Consistent with the lever arm hypothesis, the stroke size has been shown to be proportional to the lever arm length 8,9,10 . In the absence of actin, ATP hydrolysis occurs, but product release is slow, thus trapping the lever arm in a primed or pre-powerstroke position.Correspondence should be addressed to either: Anne Houdusse, Structural Motility, UMR 144 Institut Curie-CNRS, 26 rue d'ULM, 75248 Paris cedex 05, France,, Anne.Houdusse@curie.fr or H. Lee Sweeney, Dept. of Physiology, University of Penn., A700 Richards Bldg., 3700 Hamilton Walk, Philadelphia, PA 19104-6085, Tel. 215-898-8727, Fax. 215-573-2273, Lsweeney@mail.med.upenn.edu Binding to actin causes release of products, plus-end-directed movement of the lever arm, and force generation concomitant with formation of strong binding between myosin and actin.Perhaps because of their reverse directionality, myosin VI motors have a number of additional unusual features. First, the motor domain itself contains two inserts that are unique within...

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Section: Insert-2 Constitutes a Novel Calmodulin Binding Motifsupporting

confidence: 90%

The structure of the myosin VI motor reveals the mechanism of directionality reversal

Menetrey

Bahloul

Wells

et al. 2005

Nature

205

234

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“…That structure showed major differences from the X-ray crystal structure (Chattopadhyaya et al 1992;Wilson and Brunger 2000) in that the long central helix connecting two lobes is split into two helices (D and E) with a short and flexible linker between them. Similar features were later observed in the X-ray structure of a ''compact'' CaM, induced by a minor post-translational modification (Fallon and Quiocho 2003). Excluding the region of the central linker, all these structures show similar H-bond networks.…”

Section: Holocamsupporting

confidence: 72%

Solvent‐induced differentiation of protein backbone hydrogen bonds in calmodulin

et al. 2007

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In apo and holoCaM, almost half of the hydrogen bonds (H-bonds) at the protein backbone expected from the corresponding NMR or X-ray structures were not detected by h3 J NC9 couplings. The paucity of the h3 J NC9 couplings was considered in terms of dynamic features of these structures. We examined a set of seven proteins and found that protein-backbone H-bonds form two groups according to the h3 J NC9 couplings measured in solution. H-bonds that have h3 J NC9 couplings above the threshold of 0.2 Hz show distance/angle correlation among the H-bond geometrical parameters, and appear to be supported by the backbone dynamics in solution. The other H-bonds have no such correlation; they populate the waterexposed and flexible regions of proteins, including many of the CaM helices. The observed differentiation in a dynamical behavior of backbone H-bonds in apo and holoCaM appears to be related to protein functions.

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“…The existence of an ion-bound form that resembles the apo conformation has recently been established (51). Likewise, the R state is a collection of structures that resemble the reported open structure of active calmodulin (52,53). Asymmetric forms of calmodulin with one lobe in an open state and one head in a closed state have been reported in the presence of some targets (54).…”

Section: Discussionmentioning

confidence: 95%

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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A Closed Compact Structure of Native Ca2+-Calmodulin

Cited by 161 publications

References 23 publications

The structure of the myosin VI motor reveals the mechanism of directionality reversal

The structure of the myosin VI motor reveals the mechanism of directionality reversal

Solvent‐induced differentiation of protein backbone hydrogen bonds in calmodulin

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

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