New alpha IIb beta 3 variants in 28 Turkish Glanzmann patients; Structural hypothesis for complex activation by residues variations in I-EGF domains

Koker M. Y.; Sarper N.; Albayrak C.Zulfikar B.Zengin E.Saraymen B.Albayrak D.Koc B.Avcilar H.Karakukcu M.Chenet C.Bianchi F.de Brevern A. G.Petermann R.Jallu V

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New alpha IIb beta 3 variants in 28 Turkish Glanzmann patients; Structural hypothesis for complex activation by residues variations in I-EGF domains

机译：New alpha IIb beta 3 variants in 28 Turkish Glanzmann patients; Structural hypothesis for complex activation by residues variations in I-EGF domains

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摘要

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin alpha IIb beta 3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets alpha IIb beta 3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on alpha IIb beta 3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. alpha IIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired alpha IIb beta 3 expression. The alpha IIb:p.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3:c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The beta 3:p.Gly540Asp substitution allowed alpha IIb beta 3 expression in HEK-293 cells but induced its constitutive activation likely by impairing alpha IIb and beta 3 legs interaction. The substitution alters the beta 3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3:c.1752 + 2 T > C and NM_000212.2:c.1697 G > A variations identified in 4 and 8 families, respectively, might be a current cause of GT in Turkey. MD simulations suggested how some subtle structural variations in the beta 3 I-EGF domains might induce constitutive activation of alpha IIb beta 3 without altering the global domain structure.

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《Platelets》 |2022年第4期|551-561|共11页
作者
Koker M. Y.; Sarper N.; Albayrak C.Zulfikar B.Zengin E.Saraymen B.Albayrak D.Koc B.Avcilar H.Karakukcu M.Chenet C.Bianchi F.de Brevern A. G.Petermann R.Jallu V;
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作者单位

Oncol Inst,Istanbul Univ;

Fac Med,Kocaeli Univ;

Nanotechnol Res & Applicat Ctr,Erciyes UnivFac Med,Ondokuz Mayis UnivFac Med,Erciyes UnivDept Immunol Plaquettaire,Inst Natl Transfus Sanguine INTSBiol Integree Globule Rouge UMR S1134,Univ Antilles;

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正文语种英语
中图分类基础医学;
关键词
Hemostasis; Platelet; Glanzmann Thrombasthenia; Integrin alpha-IIb beta-3; Genetic variation; Molecular dynamics; Structural allostery; DISULFIDE BOND DISRUPTION; MOLECULAR-GENETIC-BASIS; CYSTEINE-RICH REPEAT; GLYCOPROTEIN IIIA; THROMBASTHENIA; INTEGRIN; MUTATION; IDENTIFICATION; EXPRESSION; ITGA2B;

New alpha IIb beta 3 variants in 28 Turkish Glanzmann patients; Structural hypothesis for complex activation by residues variations in I-EGF domains

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