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3d25

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Crystal structure of HA-1 minor histocompatibility antigen bound to human class I MHC HLA-A2Crystal structure of HA-1 minor histocompatibility antigen bound to human class I MHC HLA-A2

Structural highlights

3d25 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:HLA-A, HLAA (HUMAN), B2M, CDABP0092, HDCMA22P (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[1] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Function

[1A02_HUMAN] Involved in the presentation of foreign antigens to the immune system. [HMHA1_HUMAN] GTPase activator for the Rho-type GTPases (Potential).[15] [16] [17] [18] Precursor of the histocompatibility antigen HA-1. More generally, minor histocompatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and its expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocompatibility antigen in HLA-matched sibling marrow transplants. Specifically, mismatching for mHag HA-1 which is recognized as immunodominant, is shown to be associated with the development of severe GVHD after HLA-identical BMT. HA-1 is presented to the cell surface by MHC class I HLA-A*0201, but also by other HLA-A alleles. This complex specifically elicits donor-cytotoxic T-lymphocyte (CTL) reactivity against hematologic malignancies after treatment by HLA-identical allogenic BMT. It induces cell recognition and lysis by CTL.[19] [20] [21] [22] [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a "null allele" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.

Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition.,Nicholls S, Piper KP, Mohammed F, Dafforn TR, Tenzer S, Salim M, Mahendra P, Craddock C, van Endert P, Schild H, Cobbold M, Engelhard VH, Moss PA, Willcox BE Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3889-94. Epub 2009 Feb 20. PMID:19234124[23]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Wani MA, Haynes LD, Kim J, Bronson CL, Chaudhury C, Mohanty S, Waldmann TA, Robinson JM, Anderson CL. Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5084-9. Epub 2006 Mar 20. PMID:16549777 doi:10.1073/pnas.0600548103
  2. ↑ Gorevic PD, Munoz PC, Casey TT, DiRaimondo CR, Stone WJ, Prelli FC, Rodrigues MM, Poulik MD, Frangione B. Polymerization of intact beta 2-microglobulin in tissue causes amyloidosis in patients on chronic hemodialysis. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7908-12. PMID:3532124
  3. ↑ Argiles A, Derancourt J, Jauregui-Adell J, Mion C, Demaille JG. Biochemical characterization of serum and urinary beta 2 microglobulin in end-stage renal disease patients. Nephrol Dial Transplant. 1992;7(11):1106-10. PMID:1336137
  4. ↑ Momoi T, Suzuki M, Titani K, Hisanaga S, Ogawa H, Saito A. Amino acid sequence of a modified beta 2-microglobulin in renal failure patient urine and long-term dialysis patient blood. Clin Chim Acta. 1995 May 15;236(2):135-44. PMID:7554280
  5. ↑ Cunningham BA, Wang JL, Berggard I, Peterson PA. The complete amino acid sequence of beta 2-microglobulin. Biochemistry. 1973 Nov 20;12(24):4811-22. PMID:4586824
  6. ↑ Haag-Weber M, Mai B, Horl WH. Isolation of a granulocyte inhibitory protein from uraemic patients with homology of beta 2-microglobulin. Nephrol Dial Transplant. 1994;9(4):382-8. PMID:8084451
  7. ↑ Trinh CH, Smith DP, Kalverda AP, Phillips SE, Radford SE. Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9771-6. Epub 2002 Jul 15. PMID:12119416 doi:10.1073/pnas.152337399
  8. ↑ Stewart-Jones GB, McMichael AJ, Bell JI, Stuart DI, Jones EY. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol. 2003 Jul;4(7):657-63. Epub 2003 Jun 8. PMID:12796775 doi:10.1038/ni942
  9. ↑ Kihara M, Chatani E, Iwata K, Yamamoto K, Matsuura T, Nakagawa A, Naiki H, Goto Y. Conformation of amyloid fibrils of beta2-microglobulin probed by tryptophan mutagenesis. J Biol Chem. 2006 Oct 13;281(41):31061-9. Epub 2006 Aug 10. PMID:16901902 doi:10.1074/jbc.M605358200
  10. ↑ Eakin CM, Berman AJ, Miranker AD. A native to amyloidogenic transition regulated by a backbone trigger. Nat Struct Mol Biol. 2006 Mar;13(3):202-8. Epub 2006 Feb 19. PMID:16491088 doi:10.1038/nsmb1068
  11. ↑ Iwata K, Matsuura T, Sakurai K, Nakagawa A, Goto Y. High-resolution crystal structure of beta2-microglobulin formed at pH 7.0. J Biochem. 2007 Sep;142(3):413-9. Epub 2007 Jul 23. PMID:17646174 doi:10.1093/jb/mvm148
  12. ↑ Ricagno S, Colombo M, de Rosa M, Sangiovanni E, Giorgetti S, Raimondi S, Bellotti V, Bolognesi M. DE loop mutations affect beta2-microglobulin stability and amyloid aggregation. Biochem Biophys Res Commun. 2008 Dec 5;377(1):146-50. Epub 2008 Oct 1. PMID:18835253 doi:S0006-291X(08)01866-4
  13. ↑ Esposito G, Ricagno S, Corazza A, Rennella E, Gumral D, Mimmi MC, Betto E, Pucillo CE, Fogolari F, Viglino P, Raimondi S, Giorgetti S, Bolognesi B, Merlini G, Stoppini M, Bolognesi M, Bellotti V. The controlling roles of Trp60 and Trp95 in beta2-microglobulin function, folding and amyloid aggregation properties. J Mol Biol. 2008 May 9;378(4):887-97. Epub 2008 Mar 8. PMID:18395224 doi:10.1016/j.jmb.2008.03.002
  14. ↑ Ricagno S, Raimondi S, Giorgetti S, Bellotti V, Bolognesi M. Human beta-2 microglobulin W60V mutant structure: Implications for stability and amyloid aggregation. Biochem Biophys Res Commun. 2009 Mar 13;380(3):543-7. Epub 2009 Jan 25. PMID:19284997 doi:10.1016/j.bbrc.2009.01.116
  15. ↑ Marijt WA, Veenhof WF, Goulmy E, Willemze R, van Rood JJ, Falkenburg JH. Minor histocompatibility antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T-cell clones inhibit human hematopoietic progenitor cell growth by a mechanism that is dependent on direct cell-cell contact. Blood. 1993 Dec 15;82(12):3778-85. PMID:8260714
  16. ↑ Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J, Gratwohl A, Vogelsang GB, van Houwelingen HC, van Rood JJ. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med. 1996 Feb 1;334(5):281-5. PMID:8532022 doi:http://dx.doi.org/10.1056/NEJM199602013340501
  17. ↑ Rufer N, Wolpert E, Helg C, Tiercy JM, Gratwohl A, Chapuis B, Jeannet M, Goulmy E, Roosnek E. HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation. Transplantation. 1998 Oct 15;66(7):910-6. PMID:9798702
  18. ↑ Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA, van Luxemburg-Heys SA, Hoogeboom M, Mutis T, Drijfhout JW, van Rood JJ, Willemze R, Falkenburg JH. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2742-7. Epub 2003 Feb 24. PMID:12601144 doi:10.1073/pnas.0530192100
  19. ↑ Marijt WA, Veenhof WF, Goulmy E, Willemze R, van Rood JJ, Falkenburg JH. Minor histocompatibility antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T-cell clones inhibit human hematopoietic progenitor cell growth by a mechanism that is dependent on direct cell-cell contact. Blood. 1993 Dec 15;82(12):3778-85. PMID:8260714
  20. ↑ Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J, Gratwohl A, Vogelsang GB, van Houwelingen HC, van Rood JJ. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med. 1996 Feb 1;334(5):281-5. PMID:8532022 doi:http://dx.doi.org/10.1056/NEJM199602013340501
  21. ↑ Rufer N, Wolpert E, Helg C, Tiercy JM, Gratwohl A, Chapuis B, Jeannet M, Goulmy E, Roosnek E. HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation. Transplantation. 1998 Oct 15;66(7):910-6. PMID:9798702
  22. ↑ Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA, van Luxemburg-Heys SA, Hoogeboom M, Mutis T, Drijfhout JW, van Rood JJ, Willemze R, Falkenburg JH. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2742-7. Epub 2003 Feb 24. PMID:12601144 doi:10.1073/pnas.0530192100
  23. ↑ Nicholls S, Piper KP, Mohammed F, Dafforn TR, Tenzer S, Salim M, Mahendra P, Craddock C, van Endert P, Schild H, Cobbold M, Engelhard VH, Moss PA, Willcox BE. Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3889-94. Epub 2009 Feb 20. PMID:19234124 doi:0900411106

3d25, resolution 1.30Å

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