Molecular insight into human platelet antigens: structural and evolutionary conservation analyses offer new perspective to immunogenic disorders.
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.
Landau
Meytal
M
Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Rosenberg
Nurit
N
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
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
Vox Sang. 2003 Oct;85(3):240-5
14516468
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W299-302
15980475
Biophys J. 2008 Sep 15;95(6):2895-908
18515366
J Biol Chem. 2004 May 28;279(22):23327-34
15039442
Science. 2001 Oct 12;294(5541):339-45
11546839
J Thromb Haemost. 2009 Sep;7(9):1533-40
19566547
Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15633-8
15501918
Blood. 2002 Mar 1;99(5):1833-9
11861302
Blood. 1991 May 1;77(9):1964-9
1708295
Hum Mutat. 2006 Apr;27(4):359-69
16463284
Thromb Haemost. 1993 May 3;69(5):485-9
7686694
Thromb Haemost. 2007 Dec;98(6):1257-65
18064323
Science. 2003 Jul 11;301(5630):177-9
12855796
Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):1142-7
10195947
Science. 2003 Jul 11;301(5630):222-6
12855811
J Thromb Haemost. 2004 Jul;2(7):1167-75
15219201
Transfusion. 2010 Feb;50(2):324-33
19821948
Transfusion. 2004 Aug;44(8):1220-5
15265127
Circulation. 2000 Mar 7;101(9):1013-8
10704169
Science. 2003 Jul 11;301(5630):218-21
12855810
J Mol Evol. 2005 Mar;60(3):345-53
15871045
J Thromb Haemost. 2007 Feb;5(2):378-86
17083647
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D154-9
15608167
Thromb Haemost. 1995 Jul;74(1):234-9
8578464
Cell. 2000 Mar 31;101(1):47-56
10778855
Mol Cell. 2008 Dec 26;32(6):849-61
19111664
J Cell Biol. 2008 Aug 25;182(4):791-800
18710925
Nucleic Acids Res. 2007;35(11):3823-35
17526529
Nature. 2004 Nov 4;432(7013):59-67
15378069
Nucleic Acids Res. 1999 Jan 1;27(1):49-54
9847139
Cell. 2002 Sep 20;110(6):673-87
12297042
Am J Pharmacogenomics. 2005;5(2):93-9
15813672
BMC Bioinformatics. 2006 Mar 22;7:166
16551372
Haematologica. 2007 May;92(5):698-701
17488698
Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16221-6
16251276
Blood. 2009 Aug 27;114(9):1954-7
19494351
N Engl J Med. 1996 Apr 25;334(17):1090-4
8598867
Exp Biol Med (Maywood). 2006 May;231(5):505-13
16636298
Curr Opin Struct Biol. 1996 Jun;6(3):361-5
8804822
Blood. 2002 Feb 15;99(4):1205-14
11830467
J Biol Chem. 1994 Mar 18;269(11):8439-44
8132570
Transfusion. 2006 May;46(5):790-9
16686847
Proteins. 2003;53 Suppl 6:430-5
14579332
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Blood. 1995 Jun 1;85(11):3028-33
7756638
J Thromb Haemost. 2008 Feb;6(2):376-83
18031296
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417
Blood. 2002 Mar 1;99(5):1692-8
11861285
FASEB J. 2006 Jul;20(9):1525-7
16754747
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
15034147
Bioinformatics. 2004 May 22;20(8):1322-4
14871869