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Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains.
Anies, Sali; Jallu, Vincent; Diharce, Julien; Narwani, Tarun J; de Brevern, Alexandre G.
Afiliação
  • Anies S; INSERM, BIGR, Université de Paris and Université de la Réunion et Université des Antilles, F-75015 Paris, France.
  • Jallu V; Centre National de Référence en Hémobiologie Périnatale (CNRHP), Site St Antoine, DMU Biologie et Génomique Médicales, AP-HP, Sorbonne Université, F-75012 Paris, France.
  • Diharce J; INSERM, BIGR, Université de Paris and Université de la Réunion et Université des Antilles, F-75015 Paris, France.
  • Narwani TJ; INSERM, BIGR, Université de Paris and Université de la Réunion et Université des Antilles, F-75015 Paris, France.
  • de Brevern AG; INSERM, BIGR, Université de Paris and Université de la Réunion et Université des Antilles, F-75015 Paris, France.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article em En | MEDLINE | ID: mdl-35055046
Integrin αIIbß3, a glycoprotein complex expressed at the platelet surface, is involved in platelet aggregation and contributes to primary haemostasis. Several integrin αIIbß3 polymorphisms prevent the aggregation that causes haemorrhagic syndromes, such as Glanzmann thrombasthenia (GT). Access to 3D structure allows understanding the structural effects of polymorphisms related to GT. In a previous analysis using Molecular Dynamics (MD) simulations of αIIbCalf-1 domain structure, it was observed that GT associated with single amino acid variation affects distant loops, but not the mutated position. In this study, experiments are extended to Calf-1, Thigh, and Calf-2 domains. Two loops in Calf-2 are unstructured and therefore are modelled expertly using biophysical restraints. Surprisingly, MD revealed the presence of rigid zones in these loops. Detailed analysis with structural alphabet, the Proteins Blocks (PBs), allowed observing local changes in highly flexible regions. The variant P741R located at C-terminal of Calf-1 revealed that the Calf-2 presence did not affect the results obtained with isolated Calf-1 domain. Simulations for Calf-1 + Calf-2, and Thigh + Calf-1 variant systems are designed to comprehend the impact of five single amino acid variations in these domains. Distant conformational changes are observed, thus highlighting the potential role of allostery in the structural basis of GT.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Mutação de Sentido Incorreto / Glicoproteína IIb da Membrana de Plaquetas / Domínios e Motivos de Interação entre Proteínas Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Mutação de Sentido Incorreto / Glicoproteína IIb da Membrana de Plaquetas / Domínios e Motivos de Interação entre Proteínas Idioma: En Ano de publicação: 2022 Tipo de documento: Article