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==Crystal structure of Modified Melanoma Antigen gp100(209-T2M) Bound to Human Class I MHC HLA-A2==
==Crystal structure of Modified Melanoma Antigen gp100(209-T2M) Bound to Human Class I MHC HLA-A2==
<StructureSection load='1tvh' size='340' side='right' caption='[[1tvh]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
<StructureSection load='1tvh' size='340' side='right'caption='[[1tvh]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1tvh]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TVH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TVH FirstGlance]. <br>
<table><tr><td colspan='2'>[[1tvh]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TVH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.802&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1duz|1duz]], [[1qr1|1qr1]], [[1tvb|1tvb]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HLA-A, HLAA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), B2M ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1tvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tvh OCA], [https://pdbe.org/1tvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tvh RCSB], [https://www.ebi.ac.uk/pdbsum/1tvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tvh ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1tvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tvh OCA], [http://pdbe.org/1tvh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1tvh RCSB], [http://www.ebi.ac.uk/pdbsum/1tvh PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[http://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>
[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>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/1A02_HUMAN 1A02_HUMAN]] Involved in the presentation of foreign antigens to the immune system. [[http://www.uniprot.org/uniprot/PMEL_HUMAN PMEL_HUMAN]] Plays a central role in the biogenesis of melanosomes. Involved in the maturation of melanosomes from stage I to II. The transition from stage I melanosomes to stage II melanosomes involves an elongation of the vesicle, and the appearance within of distinct fibrillar structures. Release of the soluble form, ME20-S, could protect tumor cells from antibody mediated immunity.<ref>PMID:11694580</ref> [[http://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.  
[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>
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tv/1tvh_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tv/1tvh_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
Line 33: Line 33:


==See Also==
==See Also==
*[[Beta-2 microglobulin|Beta-2 microglobulin]]
*[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]]
*[[Major histocompatibility complex|Major histocompatibility complex]]
*[[MHC 3D structures|MHC 3D structures]]
*[[MHC I 3D structures|MHC I 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Baker, B M]]
[[Category: Large Structures]]
[[Category: Borbulevych, O Y]]
[[Category: Baker BM]]
[[Category: Hla-a2]]
[[Category: Borbulevych OY]]
[[Category: Immune system]]
[[Category: Melanoma]]
[[Category: Mhc]]
[[Category: Modified gp100 peptide]]
[[Category: X-ray]]

Latest revision as of 09:34, 23 August 2023

Crystal structure of Modified Melanoma Antigen gp100(209-T2M) Bound to Human Class I MHC HLA-A2Crystal structure of Modified Melanoma Antigen gp100(209-T2M) Bound to Human Class I MHC HLA-A2

Structural highlights

1tvh 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 1.802Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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).[1] [2] [3] [4] 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).[5] [6] 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.[7] Allele A*29:02 is associated with increased susceptibility to birdshot chorioretinopathy (BSCR). May aberrantly present retinal autoantigens and induce autoimmune uveitis.[8]

Function

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).[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] 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).[35] [36] [37] [38] [39] [40] [41] [42] [43] [44] 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.[45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] 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).[62] [63] [64] [65] [66] [67] [68] 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).[69] [70] 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.[71] 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).[72] [73] [74] [75] [76] [77] 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.[78] 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.[79] 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.[80] 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.[81] [82] [83] 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.[84]

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

The use of "anchor-fixed" altered peptide ligands is of considerable interest in the development of therapeutic vaccines for cancer and infectious diseases, but the mechanism by which successful altered peptide ligands elicit enhanced immunity is unclear. In this study, we have determined the crystallographic structure of a major tumor rejection Ag, gp100(209-217), in complex with the HLA-A*0201 (HLA-A2) molecule, as well as the structure of a modified version of the peptide which substitutes methionine for threonine at position 2 (T2M; gp100(209-2M)). The T2M-modified peptide, which is more immunogenic in vitro and in vivo, binds HLA-A2 with a approximately 9-fold greater affinity and has a approximately 7-fold slower dissociation rate at physiological temperature. Within the limit of the crystallographic data, the T2M substitution does not alter the structure of the peptide/HLA-A2 complex. Consistent with this finding, in peripheral blood from 95 human subjects, we were unable to identify higher frequencies of T cells specific for either the native or modified peptide. These data strongly support the conclusion that the greater immunogenicity of the gp100(209-2M) peptide is due to the enhanced stability of the peptide/MHC complex, validating the anchor-fixing approach for generating therapeutic vaccine candidates. Thermodynamic data suggest that the enhanced stability of the T2M-modified peptide/HLA-A2 complex is attributable to the increased hydrophobicity of the modified peptide, but the gain due to hydrophobicity is offset considerably by the loss of a hydrogen bond made by the native peptide to the HLA-A2 molecule. Our findings have broad implications for the optimization of current vaccine-design strategies.

Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design.,Borbulevych OY, Baxter TK, Yu Z, Restifo NP, Baker BM J Immunol. 2005 Apr 15;174(8):4812-20. PMID:15814707[85]

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

See Also

References

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  53. ↑ Tripathi SC, Peters HL, Taguchi A, Katayama H, Wang H, Momin A, Jolly MK, Celiktas M, Rodriguez-Canales J, Liu H, Behrens C, Wistuba II, Ben-Jacob E, Levine H, Molldrem JJ, Hanash SM, Ostrin EJ. Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1555-64. doi:, 10.1073/pnas.1521812113. Epub 2016 Feb 29. PMID:26929325 doi:http://dx.doi.org/10.1073/pnas.1521812113
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  83. ↑ Salter RD, Norment AM, Chen BP, Clayberger C, Krensky AM, Littman DR, Parham P. Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8. Nature. 1989 Mar 23;338(6213):345-7. doi: 10.1038/338345a0. PMID:2784196 doi:http://dx.doi.org/10.1038/338345a0
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  85. ↑ Borbulevych OY, Baxter TK, Yu Z, Restifo NP, Baker BM. Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design. J Immunol. 2005 Apr 15;174(8):4812-20. PMID:15814707

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