In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect

Goguet, Matthieu; Narwani, Tarun Jairaj; Petermann, Rachel; Jallu, Vincent; Brevern, Alexandre G. de

doi:10.1038/s41598-017-08408-w

Cited by 36 publications

(75 citation statements)

References 50 publications

(61 reference statements)

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“…Recently, Van Belleghem et al . 25 have shown that human immune responses to phages in vitro are predominantly anti‐inflammatory and – interestingly – moderate amounts of endotoxin can up‐regulate those effects further. The authors have shown that adding an intermediate level of endotoxin up‐regulates interleukin‐1 receptor antagonist and reduces strongly the expression of proinflammatory cytokines chemokine (C‐X‐C motif) ligand 1 (CXCL1) and CXCL5.…”

Section: Phages As Anti‐inflammatory Agentsmentioning

confidence: 99%

“…Recent findings indicate that phages induce IL‐10 production by human mononuclear cells 25. This cytokine, known for its anti‐inflammatory action, has been recognized as playing a protective role against hepatic injury.…”

Section: Phages In Potential Immunotherapy Of Aldmentioning

confidence: 99%

“…Phages have been found to up‐regulate the expression of IL‐1 receptor antagonist (IL‐1RN) 25. It is noteworthy that the evolution to a more aggressive form of chronic active hepatitis is associated with an excess of IL‐1 over IL‐1RN at tissue level 45.…”

Section: Phages In Potential Immunotherapy Of Aldmentioning

confidence: 99%

“…Inhibitors of TLR‐4 are being tested in the hope that they might prevent the progression of chronic hepatitis 48, 49. As purified phages may down‐regulate TLR‐4 25, they are an obvious candidate for such trials.…”

Section: Phages In Potential Immunotherapy Of Aldmentioning

confidence: 99%

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Therapeutic potential of phages in autoimmune liver diseases

Górski

Jończyk‐Matysiak

Łusiak-Szelachowska

et al. 2018

Clinical and Experimental Immunology

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SummaryAutoimmune liver disease (ALD) poses a difficult medical challenge, as there is a significant number of patients in whom current therapy offers questionable or no benefit, yet its side effects may be serious, including the development of malignancy. Bacterial viruses (phages) have been recognized increasingly as immunomodulators contributing to immune homeostasis and curbing inflammation. Accumulating data suggest that phages may be useful in immunotherapy of ALD. Phages have been shown to down‐regulate the expression and/or production and activity of factors associated with hepatic injury [reactive oxygen species, Toll‐like receptor (TLR)‐4 activation, nuclear factor kappa B (NF‐κB) activation, proinflammatory and procoagulant activities of platelets] and up‐regulate the expression and/or production of factors demonstrated as playing a protective role [interleukin (IL)‐10, IL‐1 receptor antagonist].

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Section: Phages As Anti‐inflammatory Agentsmentioning

confidence: 99%

Section: Phages In Potential Immunotherapy Of Aldmentioning

confidence: 99%

Section: Phages In Potential Immunotherapy Of Aldmentioning

confidence: 99%

Section: Phages In Potential Immunotherapy Of Aldmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic potential of phages in autoimmune liver diseases

Górski

Jończyk‐Matysiak

Łusiak-Szelachowska

et al. 2018

Clinical and Experimental Immunology

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“…Arg755 localizes to the upper end of a β‐strand with its side chain aligning toward the exterior limiting the short range structural effect within αIIb of its substitution by Gln or Pro. Significantly, long‐range effects were recently identiffied for these substitutions from molecular dynamics simulations (Goguet, Narwani, Petermann, Jallu, & De Brevern, ). The jury is out on whether the relatively inert Leu752Val contributes to the type I GT phenotype.…”

Section: Resultsmentioning

confidence: 99%

In silico analysis of structural modifications in and around the integrin αIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia

Pillois

Péters

Segers

et al. 2018

Molec Gen & Gen Med

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BackgroundStudies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the αIIbβ3 integrin in platelet aggregation. Stable bent αIIbβ3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The αIIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the αIIb genu define GT phenotype.MethodsSanger sequencing of ITGA2B and ITGB3 in the index case followed by in silico modeling of all known GT‐causing missense mutations extending from the lower part of the β‐propeller, and through the thigh and upper calf‐1 domains.ResultsA homozygous c.1772A>C transversion in exon 18 of ITGA2B coding for a p.Asp591Ala substitution in an interconnecting loop of the lower thigh domain of αIIb in a patient with platelets lacking αIIbβ3 led us to extend our in silico modeling to all 16 published disease‐causing missense variants potentially affecting the αIIb genu. Modifications of structuring H‐bonding were the major cause in the thigh domain although one mutation gave mRNA decay. In contrast, short‐range changes induced in calf‐1 appeared minor suggesting long‐range effects. All result in severe to total loss of αIIbβ3 in platelets. The absence of mutations within a key Ca2+‐binding loop in the genu led us to scan public databases; three potential single allele variants giving major structural changes were identiffied suggesting that this key region is not protected from genetic variation.ConclusionsIt appears that the αIIb genu is the object of stringent quality control to prevent platelets from circulating with activated and extended integrin.

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Molecular dynamics simulations corroborate recombinant expression studies carried out on three αIIb β‐propeller mutations reported in Indian Glanzmann thrombasthenia patients

Chandrasekaran,

Vishal,

Arora

et al. 2023

J of Cellular Biochemistry

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Mutations in the αIIb β‐propeller domain have long been known to disrupt heterodimerization and intracellular trafficking of αIIbβ3 complexes leading to diminished surface expression and/or function, resulting in Glanzmann thrombasthenia. Our previous study on three β‐propeller mutations, namely G128S, S287L, and G357S, showed variable defects in protein transport correlated with the patient's clinical phenotypes. Pulse‐chase experiments revealed differences in αIIbβ3 complex maturation among the three mutations. Hence, the current study aims to correlate conformational changes caused by each one of them. Evolutionary conservation analysis, stability analysis, and molecular dynamics simulations of the three mutant structures were carried out. Stability analysis revealed that, while G128S and G357S mutations destabilized the β‐propeller structure, S287L retained the stability. Wild‐type and mutant β‐propeller structures, when subjected to molecular dynamics simulations, confirmed that G128S and G357S were both destabilizing in nature when compared with the wild‐type and S287L based on several parameters studied, like RMSD, RMSF, Rg, FEL, PCA, secondary structure, and hydrogen bonds. In our previous study, we demonstrated that mutant S287L αIIbβ3 complexes were more stable than the wild‐type αIIbβ3 complexes, as evidenced in pulse‐chase experiments. These findings corroborate variable intracellular fates of mutant αIIbβ3 complexes as a result of these β‐propeller mutations.

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In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect

Cited by 36 publications

References 50 publications

Therapeutic potential of phages in autoimmune liver diseases

Therapeutic potential of phages in autoimmune liver diseases

In silico analysis of structural modifications in and around the integrin αIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia

Molecular dynamics simulations corroborate recombinant expression studies carried out on three αIIb β‐propeller mutations reported in Indian Glanzmann thrombasthenia patients

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