Protein Grabs a Ligand by Extending Anchor Residues: Molecular Simulation for Ca2+ Binding to Calmodulin Loop

Kobayashi, Chigusa; Takada, Shoji

doi:10.1529/biophysj.105.078071

Cited by 34 publications

(19 citation statements)

References 42 publications

(94 reference statements)

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“…Activation of the thin filament will be then precipitated by rotation and a re-opening of the hydrophobic pocket that can be envisioned as a reversal of the above described steps. The Ca 2+ ligands will reach [11] to grab and pull in the ion. The sidechain oxygen atoms of the site-terminal GLU and ligands 1, 3 and 5 will be attracted to the ion thus rotating the backbone, restoring the N 2 -OE 12 /N 9 -OE 12 interactions and inducing the B helix to move away from the A helix while unpacking the hydrophobic core.…”

Section: Resultsmentioning

confidence: 99%

“…EF-hand proteins have been the subject of several computational studies in recent years [10], [11], [12] and so has been another thin filament protein - actin. Deriu et al [13], [14] used atomistic and continuum scale modeling to describe the macro mechanics of actin filaments as a function of nanoscale events on the local level using molecular dynamics, coarse-grained model and normal mode analysis.…”

Section: Introductionmentioning

confidence: 99%

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Calcium Induced Regulation of Skeletal Troponin — Computational Insights from Molecular Dynamics Simulations

Genchev

Kobayashi

2013

PLoS ONE

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The interaction between calcium and the regulatory site(s) of striated muscle regulatory protein troponin switches on and off muscle contraction. In skeletal troponin binding of calcium to sites I and II of the TnC subunit results in a set of structural changes in the troponin complex, displaces tropomyosin along the actin filament and allows myosin-actin interaction to produce mechanical force. In this study, we used molecular dynamics simulations to characterize the calcium dependent dynamics of the fast skeletal troponin molecule and its TnC subunit in the calcium saturated and depleted states. We focused on the N-lobe and on describing the atomic level events that take place subsequent to removal of the calcium ion from the regulatory sites I and II. A main structural event - a closure of the A/B helix hydrophobic pocket results from the integrated effect of the following conformational changes: the breakage of H-bond interactions between the backbone nitrogen atoms of the residues at positions 2, 9 and sidechain oxygen atoms of the residue at position 12 (N2-OE12/N9-OE12) in sites I and II; expansion of sites I and II and increased site II N-terminal end-segment flexibility; strengthening of the β-sheet scaffold; and the subsequent re-packing of the N-lobe hydrophobic residues. Additionally, the calcium release allows the N-lobe to rotate relative to the rest of the Tn molecule. Based on the findings presented herein we propose a novel model of skeletal thin filament regulation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Calcium Induced Regulation of Skeletal Troponin — Computational Insights from Molecular Dynamics Simulations

Genchev

Kobayashi

2013

PLoS ONE

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“…The success of the grafting approach indicates that the loop itself, once structurally buttressed by the scaffold, is the functional motif, independent of other parts. Kobayashi and Takada [44] found that, at an early stage of binding, some key residue side chains extend their "arms" to catch Ca 2+ and, after catching, they carry the Ca 2+ to the center of the binding pocket. This grabbing motion results in smooth and stepwise exchange of the coordination partners of Ca 2+ from water oxygen to atoms in the CaM loop.…”

Section: Discussionmentioning

confidence: 99%

“…Using a molecular dynamics (MD) simulation of an all-atom model and explicit solvent molecules, Kobayashi and Takada found that the key residue that first catches the Ca 2+ ion is one of the two highly conserved acidic residues [44].…”

Section: Discussionmentioning

confidence: 99%

Calcium-induced changes in calmodulin structural dynamics and thermodynamics

Gao

Dong

et al. 2012

International Journal of Biological Macromolecules

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“…The EF-hand structure, which has a helix-loop-helix design, is the most common Ca 2ϩ -binding motif (30). AMBN has an EF-hand motif in the C-terminal region, and proteolytic peptides from that region, particularly those migrating at 27 and 29 kDa, can be seen on SDS-PAGE assays of calcium binding.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Heparin Binding Domains of Ameloblastin for Dental Epithelium Cell Adhesion and Ameloblastoma Proliferation

Sonoda

Iwamoto

Nakamura

et al. 2009

Journal of Biological Chemistry

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AMBN (ameloblastin)is an enamel matrix protein that regulates cell adhesion, proliferation, and differentiation of ameloblasts. In AMBN-deficient mice, ameloblasts are detached from the enamel matrix, continue to proliferate, and form a multiple cell layer; often, odontogenic tumors develop in the maxilla with age. However, the mechanism of AMBN functions in these biological processes remains unclear. By using recombinant AMBN proteins, we found that AMBN had heparin binding domains at the C-terminal half and that these domains were critical for AMBN binding to dental epithelial cells. Overexpression of fulllength AMBN protein inhibited proliferation of human ameloblastoma AM-1 cells, but overexpression of heparin binding domain-deficient AMBN protein had no inhibitory effect. In full-length AMBN-overexpressing AM-1 cells, the expression of Msx2, which is involved in the dental epithelial progenitor phenotype, was decreased, whereas the expression of cell proliferation inhibitors p21 and p27 was increased. We also found that the expression of enamelin, a marker of differentiated ameloblasts, was induced, suggesting that AMBN promotes odontogenic tumor differentiation. Thus, our results suggest that AMBN promotes cell binding through the heparin binding sites and plays an important role in preventing odontogenic tumor development by suppressing cell proliferation and maintaining differentiation phenotype through Msx2, p21, and p27.The extracellular matrix provides structural support for cells and regulates cell proliferation, migration, differentiation, and apoptosis for tissue development and homeostasis (1). The extracellular matrix also plays a crucial role in pathological processes and diseases, such as wound healing, tumorigenesis, and cancer development (2, 3). AMBN (ameloblastin), also known as amelin and sheathlin, is a tooth-specific extracellular matrix and the most abundant non-amelogenin enamel matrix protein (4 -6). AMBN is expressed primarily by ameloblasts, which are differentiated from the oral ectoderm and form a polarized single cell layer underlying the enamel matrix. In a previous study, we created Ambn-null mice and demonstrated that AMBN is required for cell attachment and polarization and for maintaining the differentiation state of ameloblasts and is essential for enamel formation (3). Overexpression of Ambn in transgenic mice causes abnormal enamel crystallite formation and enamel rod morphology (7). These results suggest that enamel formation and rod morphology are influenced by temporal and spatial expressions of AMBN and imply that the AMBN gene locus may be involved in the etiology of a number of cases of undiagnosed hereditary amelogenesis imperfecta (8). Further, it was reported that recombinant AMBN enhances pulpal wound healing and reparative dentine formation following pulpotomy procedures, suggesting that it functions as a signal molecule in epithelial-mesenchymal interactions (9).We previously reported that about 20% of Ambn-null mice developed an odontogenic tumor of dental ep...

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Protein Grabs a Ligand by Extending Anchor Residues: Molecular Simulation for Ca2+ Binding to Calmodulin Loop

Cited by 34 publications

References 42 publications

Calcium Induced Regulation of Skeletal Troponin — Computational Insights from Molecular Dynamics Simulations

Calcium Induced Regulation of Skeletal Troponin — Computational Insights from Molecular Dynamics Simulations

Calcium-induced changes in calmodulin structural dynamics and thermodynamics

Critical Role of Heparin Binding Domains of Ameloblastin for Dental Epithelium Cell Adhesion and Ameloblastoma Proliferation

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