αIIbβ3: structure and function

Coller, Barry S.

doi:10.1111/jth.12915

Cited by 52 publications

(45 citation statements)

References 68 publications

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“…α IIb β 3 is essential for platelet-mediated hemostasis and thrombosis 31, 32 , while α V β 3 is important in tumor angiogenesis, metastasis, and inflammation 33, 34 . It has been reported that the α V β 3 glycosylation differs significantly between primary and metastatic melanoma cells 14 .…”

Section: Introductionmentioning

confidence: 99%

The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation

Cai

Thinn

Wang

et al. 2017

Sci Rep

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N-glycosylations can regulate the adhesive function of integrins. Great variations in both the number and distribution of N-glycosylation sites are found in the 18 α and 8 β integrin subunits. Crystal structures of αIIbβ3 and αVβ3 have resolved the precise structural location of each N-glycan site, but the structural consequences of individual N-glycan site on integrin activation remain unclear. By site-directed mutagenesis and structure-guided analyses, we dissected the function of individual N-glycan sites in β3 integrin activation. We found that the N-glycan site, β3-N320 at the headpiece and leg domain interface positively regulates αIIbβ3 but not αVβ3 activation. The β3-N559 N-glycan at the β3-I-EGF3 and αIIb-calf-1 domain interface, and the β3-N654 N-glycan at the β3-β-tail and αIIb-calf-2 domain interface positively regulate the activation of both αIIbβ3 and αVβ3 integrins. In contrast, removal of the β3-N371 N-glycan near the β3 hybrid and I-EGF3 interface, or the β3-N452 N-glycan at the I-EGF1 domain rendered β3 integrin more active than the wild type. We identified one unique N-glycan at the βI domain of β1 subunit that negatively regulates α5β1 activation. Our study suggests that the bulky N-glycans influence the large-scale conformational rearrangement by potentially stabilizing or destabilizing the domain interfaces of integrin.

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Section: Introductionmentioning

confidence: 99%

The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation

Cai

Thinn

Wang

et al. 2017

Sci Rep

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“…Only stimulation by agonists at the sites of wounds turns on the fibrinogen binding function of α IIb β 3 integrins, which then leads to aggregation of platelets and the formation of a thrombus, halting the loss of blood. The transition between the ‘on’ and ‘off’ affinity states is referred to as activation (for reviews see Banno and Ginsberg 2008; Luo et al 2007; Bouaouina et al 2012; Ye et al 2012; Coller 2015). Many of the current models of integrin’s molecular activation mechanism have been primarily inferred from crystal structures of β 3 integrin extracellular domains (Xiong et al 2001, 2002, 2009; Zhu et al 2008, 2009, 2013; Dong et al 2012) as well as two-dimensional negativestain electron microscopy (Luo et al 2007; Nishida et al 2006; Takagi et al 2002; Xie et al 2010; Ye et al 2010; Zhu et al 2008; Dai et al 2015; Su et al 2016; Eng et al 2011).…”

Section: 1 Introductionmentioning

confidence: 99%

Conformational Equilibrium of Human Platelet Integrin Investigated by Three-Dimensional Electron Cryo-Microscopy

Hanein

Volkmann

2018

Subcellular Biochemistry

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Integrins are bidirectional transmembrane receptors that play central roles in hemostasis and arterial thrombosis. They have been subject to structural studies for many years, in particular using X-ray crystallography, nuclear magnetic resonance spectroscopy, and two-dimensional negative stain electron microscopy. Despite considerable progress, a full consensus on the molecular mechanism of integrin activation is still lacking. Three-dimensional reconstructions of full-length human platelet integrin αIIbβ3 in lipid-bilayer nanodiscs obtained by electron cryo-microscopy and single-particle reconstruction have shed new light on the activation process. These studies show that integrin αIIbβ3 exists in a continuous conformational equilibrium ranging from a compact nodular conformation similar to that obtained in crystal structures to a fully extended state with the leg domains separated. This equilibrium is shifted towards the extended conformation when extracellular ligands, cytosolic activators and lipid-bilayer nanodiscs are added. Addition of cytosolic activators and extracellular ligands in the absense of nanodiscs produces significantly less dramatic shifts, emphasizing the importance of the membrane bilayer in the activation process.

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“…Three agents targeting α IIb β 3 have been approved for human use in the USA, starting with abciximab, a monoclonal antibody fragment, followed by eptifibatide, a cyclic peptide, and tirofiban, a peptidomimetic molecule [28]. These drugs have shown efficacy in the adjunctive therapy to ischemic complications of percutaneous coronary interventions in a large number of randomized studies.…”

Section: Discussionmentioning

confidence: 99%

“…RUC-1 (a small molecular inhibitor of integrin α IIb β 3) only binds to the α IIb subunit but not to β 3 and does not induce conformational changes of α IIb β 3. By avoiding such a change, it is anticipated that associated thrombocytopenia, induction of fibrinogen binding, and paradoxical platelet activation would be prevented [28, 30]. RUC-2 and RUC-4 were developed following RUC-1.…”

Section: Discussionmentioning

confidence: 99%

A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3

Ding

Liu

Xie

et al. 2016

BioMed Research International

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Integrin αIIbβ3 plays a crucial role in the process of platelet aggregation. Three integrin αIIbβ3 antagonists (abciximab, eptifibatide, and tirofiban) have been approved by FDA for clinical use. Unfortunately, they all showed severe side effects such as thrombocytopenia and bleeding risk. Thus, researches on the development of more effective and safer antiplatelet agents are needed. In this manuscript we reported a novel naphthalenic derivative compound ND-1 with potent antithrombotic effect and lower bleeding risk. ND-1 inhibited ADP-, collagen-, thrombin-, and U46619-induced platelet aggregation with IC50 values of 1.29, 14.46, 12.84, and 40.24 μM, respectively. Mechanism studies indicated that ND-1 inhibited the binding of fibrinogen to integrin αIIbβ3 in a dose-dependent manner with an IC50 value of 3.12 μM. ND-1 inhibited P-selectin expression induced by ADP, collagen, thrombin, and U46619 on the surface of platelets. Additionally, this compound reduced platelets spreading to the immobilized fibrinogen. In vivo, ND-1 potently decreased thrombus formation in an arteriovenous shunt thrombosis model in rats and slightly prolonged bleeding time in a tail cutting model in mice. Taken together, our results reveal that ND-1 is a novel antagonist of αIIbβ3 with strong antithrombotic effect and lower bleeding risk.

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αIIbβ3: structure and function

Cited by 52 publications

References 68 publications

The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation

The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation

Conformational Equilibrium of Human Platelet Integrin Investigated by Three-Dimensional Electron Cryo-Microscopy

A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3

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