Motif of HLA-B*3503 peptide ligands

Steinle, Alexander; Falk, Kirsten; Rötzschke, Olaf; Gnau, Volker; Stevanović, Stefan; Jung, Günther; Schendel, Dolores J.; Rammensee, Hans‐Georg

doi:10.1007/bf00186615

Cited by 31 publications

(34 citation statements)

References 22 publications

(14 reference statements)

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“…Detailed amino acid frequency at each position is presented in the supplemental data section. The results confirm the identity of the previously reported dominant anchor residue proline in position P2 of HLA-B3501 and B*3503-associated peptides (45,46). Also, we confirmed the dominant presence of aromatic residues (tyrosine, phenylalanine) and leucine in the C-terminal positions of peptides from HLA-B3501 and -B* 3503, respectively (45, 46).…”

Section: New Hla-b35 Motifs Include Additional Anchor Positionssupporting

confidence: 90%

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Escobar

Crockett

Reyes-Vargas

et al. 2008

The Journal of Immunology

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The majority of >2000 HLA class I molecules can be clustered according to overlapping peptide binding specificities or motifs recognized by CD8 ؉ T cells. HLA class I motifs are classified based on the specificity of residues located in the P2 and the C-terminal positions of the peptide. However, it has been suggested that other positions might be relevant for peptide binding to HLA class I molecules and therefore be used for further characterization of HLA class I motifs. In this study we performed large-scale sequencing of endogenous peptides eluted from K562 cells (HLA class I null) made to express a single HLA molecule from HLA-B*3501, -B*3502, -B*3503, -B*3504, -B*3506, or -B*3508. Using sequence data from >1,000 peptides, we characterized novel peptide motifs that include dominant anchor residues extending to all positions in the peptide. The length distribution of HLA-B35-bound peptides included peptides of up to 15 residues. Remarkably, we determined that some peptides longer than 11 residues represented N-terminal-extended peptides containing an appropriate HLA-B35 peptide motif. These results provide evidence for the occurrence of endogenous N-terminal-extended peptide-HLA class I configurations. In addition, these results expand the knowledge about the identity of anchor positions in HLA class I-associated peptides that can be used for characterization of HLA class I motifs.

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Section: New Hla-b35 Motifs Include Additional Anchor Positionssupporting

confidence: 90%

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Escobar

Crockett

Reyes-Vargas

et al. 2008

The Journal of Immunology

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“…It is also possible that contaminating peptides bound to HLA-B*35:03 were present in our dataset because, in contrast to C*04:01, B35 ligands were not filtered out during data analysis. However, only 8 out of the 2246 reported sequences (0.36%) matched the HLA-B*35:03 binding motif (43). This is consistent with the very low expression level of HLA-B35 in C1R cells caused by a point mutation in its translation initiation codon (21).…”

Section: To Test This Hypothesis the Natural Ligands S[ps]ygnirav Ansupporting

confidence: 60%

Increased Diversity of the HLA-B40 Ligandome by the Presentation of Peptides Phosphorylated at Their Main Anchor Residue

Marcilla

Alpízar

Lombardía

et al. 2014

Molecular & Cellular Proteomics

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Human leukocyte antigen (HLA) class I molecules bind peptides derived from the intracellular degradation of endogenous proteins and present them to cytotoxic T lymphocytes, allowing the immune system to detect transformed or virally infected cells. It is known that HLA class I-associated peptides may harbor posttranslational modifications. In particular, phosphorylated ligands have raised much interest as potential targets for cancer immunotherapy. By combining affinity purification with highresolution mass spectrometry, we identified more than 2000 unique ligands bound to HLA-B40. Sequence analysis revealed two major anchor motifs: aspartic or glutamic acid at peptide position 2 (P2) and methionine, phenylalanine, or aliphatic residues at the C terminus. The use of immobilized metal ion and TiO 2 affinity chromatography allowed the characterization of 85 phosphorylated ligands. We further confirmed every sequence belonging to this subset by comparing its experimental MS2 spectrum with that obtained upon fragmentation of the corresponding synthetic peptide. Remarkably, three phospholigands lacked a canonical anchor residue at P2, containing phosphoserine instead. Binding assays showed that these peptides bound to HLA-B40 with high affinity. Together, our data demonstrate that the peptidome of a given HLA allotype can be broadened by the presentation of peptides with posttranslational modifications at major anchor positions. We suggest that ligands with phosphorylated residues at P2 might be optimal targets for T-cell-based cancer immunotherapy. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.034314, 462-474, 2014. Major histocompatibility complex (MHC)1 class I molecules are cell surface glycoproteins that are expressed on almost every nucleated cell in vertebrates. They result from the noncovalent interaction of a polymorphic heavy chain, a constant light chain (␤-2-microglobulin (␤2m)), and a peptide ligand (1). The extracellular region of the heavy chain encompasses three domains, ␣ 1 , ␣ 2 , and ␣ 3 , with ␣ 1 and ␣ 2 forming a groove that accommodates a peptide ligand of, typically, 8 to 11 amino acid residues. The binding of the ligand to the groove is governed by the interaction of the side chains of certain peptide residues, called anchor positions, with several pockets of the heavy chain named A to F (1, 2). The size and chemical nature of these pockets impose restrictions on the peptide repertoire that can be associated with a particular class I antigen. It is reckoned that the ligandome of a given class I allotype may comprise up to 10,000 different peptides (3), although recent reports suggest that this number may be underestimated (4).Peptides displayed by MHC class I molecules derive from the intracellular degradation of endogenous proteins in the nucleus and cytosol and reach the lumen of the endoplasmic reticulum by means of the transporter associated with antigen processing. Inside the endoplasmic reticulum, peptides bind to the heavy chain and ␤2m in a multistep process involving several c...

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“…Database searching on the peptidome data allowed the identification of 7375 unique peptides at a FDR Ͻ 1% (supplemental Data S1). Of them, 70 (1%), 214 (3%) and 6674 (91%) were classified as B*35, C*04 or B*40 ligands, respectively, according to the binding motif reported for these molecules (8,(33)(34)(35). Only 417 sequences (6%) could not be confidently assigned to any allotype.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 1128 unique peptides of eight to 13 residues long were identified at a FDR Յ 1% at the peptide level (supplemental Data S5). Of them, 953 (84%) had His or Arg at P2, the canonical binding motif of this allele (14, 38) whereas 14 (1%) and 53 (5%) matched respectively the binding motifs of HLA-B*35 (33) and HLA-C*04 (34,35). The remaining 108 sequences (10%) could not be confidently assigned to any allotype.…”

Section: Structures Of Hla-b*40 In Complex With An Endogenous Phosphomentioning

confidence: 99%

A Molecular Basis for the Presentation of Phosphorylated Peptides by HLA-B Antigens

Alpízar

Marino

Ramos-Fernández

et al. 2017

Molecular & Cellular Proteomics

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Motif of HLA-B*3503 peptide ligands

Cited by 31 publications

References 22 publications

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs

Increased Diversity of the HLA-B40 Ligandome by the Presentation of Peptides Phosphorylated at Their Main Anchor Residue

A Molecular Basis for the Presentation of Phosphorylated Peptides by HLA-B Antigens

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