title: Molecular insight into human platelet antigens: structural and evolutionary conservation analyses offer new perspective to immunogenic disorders.
abstract: BACKGROUND
  Human platelet antigens (HPAs) are polymorphisms in platelet membrane glycoproteins (GPs) that can stimulate production of alloantibodies once exposed to foreign platelets (PLTs) with different HPAs. These antibodies can cause neonatal alloimmune thrombocytopenia, posttransfusion purpura, and PLT transfusion refractoriness. Most HPAs are localized on the main PLT receptors: 1) integrin αIIbβ3, known as the fibrinogen receptor; 2) the GPIb-IX-V complex that functions as the receptor for von Willebrand factor; and 3) integrin α2β1, which functions as the collagen receptor.
  
  
  METHODS
  We analyzed the structural location and the evolutionary conservation of the residues associated with the HPAs to characterize the features that induce immunologic responses but do not cause inherited diseases.
  
  
  RESULTS
  We found that all HPAs reside in positions located on the protein surface, apart from the ligand-binding site, and are evolutionary variable.
  
  
  CONCLUSIONS
  Disease-causing mutations often reside in highly conserved and buried positions. In contrast, the HPAs affect residues on the protein surface that were not conserved throughout evolution; this explains their naive effect on the protein function. Nonetheless, the HPAs involve substitutions of solvent-exposed positions that lead to altered interfaces on the surface of the protein and might present epitopes foreign to the immune system.
authors.affiliation: Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Meytal
authors.initials: M
authors.lastname: Landau
authors.forename: Nurit
authors.initials: N
authors.lastname: Rosenberg
mesh_terms: D015703:Antigens, CD / Q000235:genetics; D016824:Antigens, Human Platelet / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins / Q000235:genetics; D006801:Humans; D007154:Immune System Diseases / Q000209:etiology*; D039661:Integrin beta3 / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics; D011110:Polymorphism, Genetic
chemical_list: D015703:Antigens, CD; D016824:Antigens, Human Platelet; C120523:CD109 protein, human; D058851:GPI-Linked Proteins; D039661:Integrin beta3; D009363:Neoplasm Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D040201:Platelet Membrane Glycoprotein IIb
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