Integrin αIIbβ3 intermediates: From molecular dynamics to adhesion assembly

Tong, Dudu; Soley, Nidhi; Kolasangiani, Reza; Schwartz, Martin A.; Bidone, Tamara C.

doi:10.1016/j.bpj.2022.12.032

Cited by 8 publications

(10 citation statements)

References 62 publications

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“…Again, energy minimization for 15k steps and a 1ns NVT as previously described were run in GROMACS prior to the 100ns NPT simulation. Extensional stiffness, k , for each molecule was calculated using: where k B T is Boltzmann’s constant, T = 310 K, L ( t ) is the length of the reaction coordinate at time, t , and <> denotes the time average (31). For α 5 , the center-of-mass distance between D154 (synergy site binding residue) and D603 (connects to lower integrin legs) in α 5 was chosen as the length of the reaction coordinate.…”

Section: Methodsmentioning

confidence: 99%

Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion

Montes,

Barroso,

Wang

et al. 2023

Preprint

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Cells intricately sense mechanical forces from their surroundings, driving biophysical and biochemical activities. This mechanosensing phenomenon occurs at the cell-matrix interface, where mechanical forces resulting from cellular motion, such as migration or matrix stretching, are exchanged through surface receptors, primarily integrins, and their corresponding matrix ligands. A pivotal player in this interaction is the α5β1 integrin and fibronectin (FN) bond, known for its instrumental role in establishing new cell adhesion sites for migration. However, upregulation of the α5β1-FN bond is associated with uncontrolled cell metastasis. This bond operates through catch bond dynamics, wherein the bond lifetime paradoxically increases with greater force. The mechanism sustaining the characteristic catch bond dynamics of α5β1-FN remains unclear. Leveraging molecular dynamics simulations, our approach unveils a pivot-clip mechanism. Two key binding sites on FN, namely the synergy site and the RGD (arg-gly-asp) motif, act as active points for structural changes in α5β1 integrin. Conformational adaptations at these sites are induced by a series of hydrogen bond formations and breaks at the synergy site. We disrupt these adaptations through a double mutation on FN, known to reduce cell adhesion. A whole-cell finite element model is employed to elucidate how the synergy site may promote dynamic α5β1-FN binding, resisting cell contraction. In summary, our study integrates molecular and cellular-level modeling to propose that FN's synergy site reinforces cell adhesion through enhanced binding properties and a mechanosensitive pivot-clip mechanism. This work sheds light on the intricate interplay between mechanical forces and cell-matrix interactions, contributing to our understanding of cellular behaviors in physiological and pathological contexts.

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Section: Methodsmentioning

confidence: 99%

Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion

Montes,

Barroso,

Wang

et al. 2023

Preprint

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“…Its ligand-binding affinity is regulated by conformational modifications. 15 Inactive αIIbβ3 integrin adopts a bend conformation with a closed headpiece. During αIIbβ3 integrin activation, ectodomain is expanded to form an extended-closed conformation which is followed by a headpiece opening to reach an extended-open (EO) conformation.…”

Section: αIibβ3 Integrinmentioning

confidence: 99%

Platelet Mechanotransduction: Regulatory Cross Talk Between Mechanosensitive Receptors and Calcium Channels

Mammadova‐Bach

Gudermann

Braun

2023

ATVB

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Blood flow–induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating cells, triggering the rapid activation of receptors, calcium channels, and related signaling mechanisms. Shear stress can also modify the folding of extracellular molecules and directly activate mechanosensitive receptors and calcium channels. The mechanical movement of the ECM (extracellular matrix) and the intracellular cortical actin cytoskeleton can change the conformation of platelet receptors and gate channel pores in the plasma membrane. Mechanosensitive platelet receptors and their downstream signaling events and metabolic products can also indirectly activate calcium channels. While the molecular composite of mechanotransduction pathways has been described in mammals, shear stress–induced platelet receptors and their cross talk with calcium channels have been incompletely characterized. In this review, we discuss current knowledge about the role of mechanosensitive platelet receptors and calcium channels in shear-dependent platelet activation and arterial thrombus formation.

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“…Recently, Tong et al revealed the importance of an intermediate structure between active and nonactive conformation for platelet adhesion by the use of molecular dynamic (MD) calculations. 12 However, the stability of the structure of the integrin α IIb β 3 incorporated into the lipid membrane with the nonactive state of extracellular domain still needs to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

“… 16 17 Specific biological functions of platelets such as adhesion on VWF under high shear stress conditions 18 19 were also simulated from dynamic movements of atoms. 20 21 The MD simulation calculation has also been applied in parts of integrin α IIb β 3 previously 22 and, recently, for whole molecules incorporated into lipid membrane by Tong et al 12 Several previous studies revealed the important regions within the extracellular domain of α IIb β 3 to achieve its biological functions. 23 24 Moreover, the MD simulation was also applied to the intracellular domain of α IIb β 3 .…”

Section: Introductionmentioning

confidence: 99%

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Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin αIIbβ3 (Platelet Membrane Glycoprotein: GPIIb–IIIa)

Nakayama,

Goto,

Goto

2024

TH Open

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The structure and functions of the extracellular domain of platelet Integrin αIIbβ3 (platelet membrane glycoprotein: GPIIb-IIIa) change substantially upon platelet activation. However, the stability of the integrated model of extracellular/transmembrane/intracellular domains of integrin αIIbβ3 with inactive state of extracellular domain has not been clarified. The integrated model of Integrin αIIbβ3 was developed by combining the extracellular domain adopted from crystal structure and the transmembrane and intracellular domain obtained by NMR. The trans-membrane domain was settled into the phosphatidylcholine (POPC) lipid bilayer model. The position coordinates and velocity vectors of all atoms and water molecules around them were calculated by molecular dynamic simulation with the use of CHARMM (Chemistry at HARvard Macromolecular Mechanics) force field in every 2 x 10-15 sec. The root-mean-square deviations (RMSDs) of atoms constructing the integrated αIIbβ3 model apparently stabilized at approximately after 200 ns of calculation. However, minor fluctuation persisted during the entire calculation period of 650 ns. The RMSD of both αIIbβ3 showed similar trends before 200 ns. The RMSD of β3 3 apparently stabilized approximately at 400 ns with persisting minor fluctuation afterward while the structural fluctuation in αIIb persisted throughout the 650 ns calculation period. In conclusion, the integrated model of the intra-cellular, trans-membrane, and extra-cellular domain of integrin αIIb suggested persisting fluctuation even after convergence of molecular dynamic calculation.

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Integrin αIIbβ3 intermediates: From molecular dynamics to adhesion assembly

Cited by 8 publications

References 62 publications

Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion

Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion

Platelet Mechanotransduction: Regulatory Cross Talk Between Mechanosensitive Receptors and Calcium Channels

Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin αIIbβ3 (Platelet Membrane Glycoprotein: GPIIb–IIIa)

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