High-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation

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Abstract
Integrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by ‘bent/closed’ to ‘extended/open’ conformational changes. Integrin αIIbβ3, being crucial for platelet activation and aggregation, is a therapeutic target for bleeding disorders and thrombosis. Human Platelet Antigen-1a (HPA-1a) on β3 is recognized by pregnancy-associated maternal alloantibodies, potentially causing fetal/neonatal alloimmune thrombocytopenia (FNAIT) and even intracranial hemorrhage or perinatal death. However, severe disease determinants are largely unknown. We report the first structure of an anti-HPA-1a antibody fragment (Fab 26.4) in complex with integrin αIIbβ3 at high resolution by cryo-electron microscopy. Fab 26.4 binding traps αIIbβ3 in the inactive, bent/closed conformation, is incompatible with integrin extension, and inhibits αIIbβ3-dependent fibrinogen binding and platelet aggregation. Thus, anti-HPA-1a antibodies directly impair integrin activation by preventing required conformational changes. These insights will improve FNAIT diagnostics and treatment, and spark the development of novel allosteric inhibitors against β3 integrins for future therapeutic applications.
Funding Information
  • Landsteiner Foundation for Blood Transfusion Research (2019)
  • Landsteiner Foundation for Blood Transfusion Research (2336)
  • Agencia Estatal de Investigacion and European Regional Development Fund (PID2022-136322NB-I00)
  • Education Ministry of the Castilla y León autonomous government and European Regional Development Fund (CLU-2023-2-01)
  • INSTRUCT-ERIC (34459)
  • INSTRUCT-ERIC (37638)
  • INSTRUCT-ERIC (68606)

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