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== Disease ==
== Disease ==
[https://www.uniprot.org/uniprot/HLAA_HUMAN HLAA_HUMAN] Selection of immunotherapy in solid cancer;Birdshot chorioretinopathy;Prediction of phenytoin or carbamazepine toxicity. Alleles A*02:01 and A*24:02 are associated with increased susceptibility to diabetes mellitus, insulin-dependent (IDDM) (PubMed:22245737, PubMed:18802479, PubMed:16731854, PubMed:22522618). In a glucose-dependent way, allele A*02:01 may aberrantly present the signal peptide of preproinsulin (ALWGPDPAAA) on the surface of pancreatic beta cells to autoreactive CD8-positive T cells, potentially driving T-cell mediated cytotoxicity in pancreatic islets (PubMed:22245737, PubMed:18802479). Allele A*24:02 may present the signal peptide of preproinsulin (LWMRLLPLL) and contribute to acute pancreatic beta-cell destruction and early onset of IDDM (PubMed:16731854, PubMed:22522618).<ref>PMID:16731854</ref> <ref>PMID:18802479</ref> <ref>PMID:22245737</ref> <ref>PMID:22522618</ref>   Allele A*03:01 is associated with increased susceptibility to multiple sclerosis (MS), an autoimmune disease of the central nervous system (PubMed:10746785). May contribute to the initiation phase of the disease by presenting myelin PLP1 self-peptide (KLIETYFSK) to autoreactive CD8-positive T cells capable of initiating the first autoimmune attacks (PubMed:18953350).<ref>PMID:10746785</ref> <ref>PMID:18953350</ref>   Allele A*26:01 is associated with increased susceptibility to Behcet disease (BD) in the Northeast Asian population. Especially in the HLA-B*51-negative BD populations, HLA-A*26 is significantly associated with the onset of BD.<ref>PMID:30872678</ref>   Allele A*29:02 is associated with increased susceptibility to birdshot chorioretinopathy (BSCR). May aberrantly present retinal autoantigens and induce autoimmune uveitis.<ref>PMID:1728143</ref>  
[https://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[https://omim.org/entry/241600 241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.<ref>PMID:16549777</ref>  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.<ref>PMID:3532124</ref> <ref>PMID:1336137</ref> <ref>PMID:7554280</ref> <ref>PMID:4586824</ref> <ref>PMID:8084451</ref> <ref>PMID:12119416</ref> <ref>PMID:12796775</ref> <ref>PMID:16901902</ref> <ref>PMID:16491088</ref> <ref>PMID:17646174</ref> <ref>PMID:18835253</ref> <ref>PMID:18395224</ref> <ref>PMID:19284997</ref>  
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/HLAA_HUMAN HLAA_HUMAN] Antigen-presenting major histocompatibility complex class I (MHCI) molecule. In complex with B2M/beta 2 microglobulin displays primarily viral and tumor-derived peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-A-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected or transformed cells (PubMed:2456340, PubMed:2784196, PubMed:1402688, PubMed:7504010, PubMed:9862734, PubMed:10449296, PubMed:12138174, PubMed:12393434, PubMed:15893615, PubMed:17189421, PubMed:19543285, PubMed:21498667, PubMed:24192765, PubMed:7694806, PubMed:24395804, PubMed:28250417). May also present self-peptides derived from the signal sequence of secreted or membrane proteins, although T cells specific for these peptides are usually inactivated to prevent autoreactivity (PubMed:25880248, PubMed:7506728, PubMed:7679507). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (PubMed:12796775, PubMed:18275829, PubMed:19542454, PubMed:28250417). Typically presents intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via IFNG-induced immunoproteasome or via endopeptidase IDE/insulin-degrading enzyme (PubMed:17189421, PubMed:20364150, PubMed:17079320, PubMed:26929325, PubMed:27049119). Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9 (PubMed:7504010, PubMed:9862734).<ref>PMID:10449296</ref> <ref>PMID:12138174</ref> <ref>PMID:12393434</ref> <ref>PMID:12796775</ref> <ref>PMID:1402688</ref> <ref>PMID:15893615</ref> <ref>PMID:17079320</ref> <ref>PMID:17189421</ref> <ref>PMID:18275829</ref> <ref>PMID:19542454</ref> <ref>PMID:19543285</ref> <ref>PMID:20364150</ref> <ref>PMID:21498667</ref> <ref>PMID:24192765</ref> <ref>PMID:24395804</ref> <ref>PMID:2456340</ref> <ref>PMID:25880248</ref> <ref>PMID:26929325</ref> <ref>PMID:27049119</ref> <ref>PMID:2784196</ref> <ref>PMID:28250417</ref> <ref>PMID:7504010</ref> <ref>PMID:7506728</ref> <ref>PMID:7679507</ref> <ref>PMID:7694806</ref> <ref>PMID:9862734</ref>  Allele A*01:01: Presents a restricted peptide repertoire including viral epitopes derived from IAV NP/nucleoprotein (CTELKLSDY), IAV PB1/polymerase basic protein 1 (VSDGGPNLY), HAdV-11 capsid L3/hexon protein (LTDLGQNLLY), SARS-CoV-2 3a/ORF3a (FTSDYYQLY) as well as tumor peptide antigens including MAGE1 (EADPTGHSY), MAGEA3 (EVDPIGHLY) and WT1 (TSEKRPFMCAY), all having in common a canonical motif with a negatively charged Asp or Glu residue at position 3 and a Tyr anchor residue at the C-terminus (PubMed:1402688, PubMed:7504010, PubMed:17189421, PubMed:20364150, PubMed:25880248, PubMed:30530481, PubMed:19177349, PubMed:24395804, PubMed:26758806, PubMed:32887977). A number of HLA-A*01:01-restricted peptides carry a post-translational modification with oxidation and N-terminal acetylation being the most frequent (PubMed:25880248). Fails to present highly immunogenic peptides from the EBV latent antigens (PubMed:18779413).<ref>PMID:1402688</ref> <ref>PMID:17189421</ref> <ref>PMID:18779413</ref> <ref>PMID:19177349</ref> <ref>PMID:20364150</ref> <ref>PMID:24395804</ref> <ref>PMID:25880248</ref> <ref>PMID:26758806</ref> <ref>PMID:30530481</ref> <ref>PMID:7504010</ref>  Allele A*02:01: A major allele in human populations, presents immunodominant viral epitopes derived from IAV M/matrix protein 1 (GILGFVFTL), HIV-1 env (TLTSCNTSV), HIV-1 gag-pol (ILKEPVHGV), HTLV-1 Tax (LLFGYPVYV), HBV C/core antigen (FLPSDFFPS), HCMV UL83/pp65 (NLVPMVATV) as well as tumor peptide antigens including MAGEA4 (GVYDGREHTV), WT1 (RMFPNAPYL) and CTAG1A/NY-ESO-1 (SLLMWITQC), all having in common hydrophobic amino acids at position 2 and at the C-terminal anchors.<ref>PMID:11502003</ref> <ref>PMID:12138174</ref> <ref>PMID:12796775</ref> <ref>PMID:17079320</ref> <ref>PMID:18275829</ref> <ref>PMID:19542454</ref> <ref>PMID:20619457</ref> <ref>PMID:22245737</ref> <ref>PMID:26929325</ref> <ref>PMID:2784196</ref> <ref>PMID:28250417</ref> <ref>PMID:7694806</ref> <ref>PMID:7935798</ref> <ref>PMID:8630735</ref> <ref>PMID:8805302</ref> <ref>PMID:8906788</ref> <ref>PMID:9177355</ref>  Allele A*03:01: Presents viral epitopes derived from IAV NP (ILRGSVAHK), HIV-1 nef (QVPLRPMTYK), HIV-1 gag-pol (AIFQSSMTK), SARS-CoV-2 N/nucleoprotein (KTFPPTEPK) as well as tumor peptide antigens including PMEL (LIYRRRLMK), NODAL (HAYIQSLLK), TRP-2 (RMYNMVPFF), all having in common hydrophobic amino acids at position 2 and Lys or Arg anchor residues at the C-terminus (PubMed:7504010, PubMed:7679507, PubMed:9862734, PubMed:19543285, PubMed:21943705, PubMed:2456340, PubMed:32887977). May also display spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119).<ref>PMID:19543285</ref> <ref>PMID:21943705</ref> <ref>PMID:2456340</ref> <ref>PMID:27049119</ref> <ref>PMID:7504010</ref> <ref>PMID:7679507</ref> <ref>PMID:9862734</ref>  Allele A*11:01: Presents several immunodominant epitopes derived from HIV-1 gag-pol and HHV-4 EBNA4, containing the peptide motif with Val, Ile, Thr, Leu, Tyr or Phe at position 2 and Lys anchor residue at the C-terminus. Important in the control of HIV-1, EBV and HBV infections (PubMed:10449296). Presents an immunodominant epitope derived from SARS-CoV-2 N/nucleoprotein (KTFPPTEPK) (PubMed:32887977).<ref>PMID:10449296</ref> <ref>PMID:32887977</ref>  Allele A*23:01: Interacts with natural killer (NK) cell receptor KIR3DL1 and may contribute to functional maturation of NK cells and self-nonself discrimination during innate immune response.<ref>PMID:17182537</ref>  Allele A*24:02: Presents viral epitopes derived from HIV-1 nef (RYPLTFGWCF), EBV lytic- and latent-cycle antigens BRLF1 (TYPVLEEMF), BMLF1 (DYNFVKQLF) and LMP2 (IYVLVMLVL), SARS-CoV nucleocapsid/N (QFKDNVILL), as well as tumor peptide antigens including PRAME (LYVDSLFFL), all sharing a common signature motif, namely an aromatic residue Tyr or Phe at position 2 and a nonhydrophobic anchor residue Phe, Leu or Iso at the C-terminus (PubMed:9047241, PubMed:12393434, PubMed:24192765, PubMed:20844028). Interacts with natural killer (NK) cell receptor KIR3DL1 and may contribute to functional maturation of NK cells and self-nonself discrimination during innate immune response (PubMed:17182537, PubMed:18502829).<ref>PMID:12393434</ref> <ref>PMID:17182537</ref> <ref>PMID:18502829</ref> <ref>PMID:20844028</ref> <ref>PMID:24192765</ref> <ref>PMID:9047241</ref>  Allele A*26:01: Presents several epitopes derived from HIV-1 gag-pol (EVIPMFSAL, ETKLGKAGY) and env (LVSDGGPNLY), carrying as anchor residues preferentially Glu at position 1, Val or Thr at position 2 and Tyr at the C-terminus.<ref>PMID:15893615</ref>  Allele A*29:02: Presents peptides having a common motif, namely a Glu residue at position 2 and Tyr or Leu anchor residues at the C-terminus.<ref>PMID:8622959</ref>  Allele A*32:01: Interacts with natural killer (NK) cell receptor KIR3DL1 and may contribute to functional maturation of NK cells and self-nonself discrimination during innate immune response.<ref>PMID:17182537</ref>  Allele A*68:01: Presents viral epitopes derived from IAV NP (KTGGPIYKR) and HIV-1 tat (ITKGLGISYGR), having a common signature motif namely, Val or Thr at position 2 and positively charged residues Arg or Lys at the C-terminal anchor.<ref>PMID:1448153</ref> <ref>PMID:1448154</ref> <ref>PMID:2784196</ref>  Allele A*74:01: Presents immunodominant HIV-1 epitopes derived from gag-pol (GQMVHQAISPR, QIYPGIKVR) and rev (RQIHSISER), carrying an aliphatic residue at position 2 and Arg anchor residue at the C-terminus. May contribute to viral load control in chronic HIV-1 infection.<ref>PMID:21498667</ref>
[https://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/my/3myj_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/my/3myj_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
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Latest revision as of 13:12, 6 November 2024

Human Class I MHC HLA-A2 in complex with the WT-1 (126-134) (R1Y) peptide variant.Human Class I MHC HLA-A2 in complex with the WT-1 (126-134) (R1Y) peptide variant.

Structural highlights

3myj is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.89Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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

Presentation of peptides by class I or class II major histocompatibility complex (MHC) molecules is required for the initiation and propagation of a T cell-mediated immune response. Peptides from the Wilms Tumor 1 transcription factor (WT1), upregulated in many hematopoetic and solid tumors, can be recognized by T cells and numerous efforts are underway to engineer WT1-based cancer vaccines. Here we determined the structures of the class I MHC molecule HLA-A*0201 bound to the native 126-134 epitope of the WT1 peptide and a recently described variant (R1Y) with improved MHC binding. The R1Y variant, a potential vaccine candidate, alters the positions of MHC charged side chains near the peptide N-terminus and significantly reduces the peptide/MHC electrostatic surface potential. These alterations indicate that the R1Y variant is an imperfect mimic of the native WT1 peptide, and suggest caution in its use as a therapeutic vaccine. Stability measurements revealed how the R1Y substitution enhances MHC binding affinity, and together with the structures suggest a strategy for engineering WT1 variants with improved MHC binding that retain the structural features of the native peptide/MHC complex.

Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics.,Borbulevych OY, Do P, Baker BM Mol Immunol. 2010 Sep;47(15):2519-24. Epub 2010 Jul 8. PMID:20619457[15]

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. ↑ Borbulevych OY, Do P, Baker BM. Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics. Mol Immunol. 2010 Sep;47(15):2519-24. Epub 2010 Jul 8. PMID:20619457 doi:10.1016/j.molimm.2010.06.005

3myj, resolution 1.89Å

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