title: Modeling and molecular dynamics simulations of the V33 variant of the integrin subunit β3: Structural comparison with the L33 (HPA-1a) and P33 (HPA-1b) variants.
abstract: The human platelet alloantigen (HPA)-1 system, the first cause of alloimmune thrombocytopenia in Caucasians, results from leucine-to-proline substitution (alleles 1a and 1b) of residue 33 in β3 subunit of the integrin αIIbβ3. A third variant with a valine (V33) has been described. Although leucine and valine share similar physicochemical properties, sera containing alloantibodies to the HPA-1a antigen variably reacted with V33-β3, suggesting structural alterations of β3. To analyze the effect of the L33V transition, molecular dynamics simulations were performed on a 3D structural model of the V33 form of the whole β3 extracellular domain (690 residues). Dynamics of the PSI (carrying residue 33), I-EGF-1, and I-EGF-2 domains of β3 were compared to previously obtained dynamics of HPA-1a structure and HPA-1b structural model using classical and innovative developments (a structural alphabet). Clustering approach and local structure analysis showed that L33-β3 and V33-β3 mostly share common structures co-existing in different dynamic equilibria. The L33V substitution mainly displaces the equilibrium between common structures. These observations can explain the variable reactivity of anti-HPA-1a alloantibodies suggesting that molecular dynamic plays a key role in the binding of these alloantibodies. Unlike the L33P substitution, the L33V transition would not affect the structure flexibility of the β3 knee, and consequently the functions of αIIbβ3.
authors.affiliation: Institut National de la Transfusion Sanguine (INTS), Département d'Immunologie Plaquettaire, F-75015 Paris, France. Electronic address: vjallu@ints.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jallu
authors.affiliation: INSERM, U 1134, DSIMB, F-75739 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, F-75739 Paris, France; Institut National de la Transfusion Sanguine (INTS), F-75739 Paris, France; Laboratoire d'Excellence GR-Ex, F-75739 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Poulain
authors.affiliation: INSERM, U 1134, DSIMB, F-75739 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, F-75739 Paris, France; Institut National de la Transfusion Sanguine (INTS), F-75739 Paris, France; Laboratoire d'Excellence GR-Ex, F-75739 Paris, France.
authors.forename: Patrick F J
authors.initials: PF
authors.lastname: Fuchs
authors.affiliation: Institut National de la Transfusion Sanguine (INTS), Département d'Immunologie Plaquettaire, F-75015 Paris, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Kaplan
authors.affiliation: INSERM, U 1134, DSIMB, F-75739 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMR_S1134, F-75739 Paris, France; Institut National de la Transfusion Sanguine (INTS), F-75739 Paris, France; Laboratoire d'Excellence GR-Ex, F-75739 Paris, France. Electronic address: alexandre.debrevern@univ-paris-diderot.fr.
authors.forename: Alexandre G
authors.initials: AG
authors.lastname: de Brevern
mesh_terms: D016824:Antigens, Human Platelet / Q000737:chemistry* / Q000235:genetics; D001792:Blood Platelets / Q000737:chemistry*; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D039661:Integrin beta3; D007518:Isoantibodies / Q000276:immunology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000235:genetics; D013921:Thrombocytopenia
chemical_list: D016824:Antigens, Human Platelet; D000939:Epitopes; C061248:ITGB3 protein, human; D039661:Integrin beta3; D007518:Isoantibodies; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C083451:human platelet antigen 1b
keywords: HPA-1; Integrin alphaIIb beta3; Molecular dynamics simulation; Platelet; V33-beta3 antigenicity