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From Proteopedia
Enhanced MHC class I binding and immune responses through anchor modification of the non-canonical tumor associated MUC1-8 peptide
Structural highlights
Disease[MUC1_HUMAN] Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes. Function[HA1B_MOUSE] Involved in the presentation of foreign antigens to the immune system. [MUC1_HUMAN] The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.[1] [2] [3] [4] [5] [6] [7] [8] [9] The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein-protein interactions. Modulates signaling in ERK, SRC and NF-kappa-B pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates TP53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of TP53 and represses TP53 activity.[10] [11] [12] [13] [14] [15] [16] [17] [18] [B2MG_MOUSE] 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 PubMedDesigning peptide-based vaccines for therapeutic applications in cancer immunotherapy requires detailed knowledge of the interactions between the antigenic peptide and major histocompatibility complex (MHC) in addition to that between the peptide-MHC complex and the T-cell receptor. Past efforts to immunize with high-affinity tumour-associated antigenic peptides have not been very immunogenic, which may be attributed to the lack of T cells to these peptides, having been deleted during thymic development. For this reason, low-to-medium affinity non-canonical peptides represent more suitable candidates. However, in addition to the difficulty in identifying such antigens, peptide binding to MHC, and hence its ability to induce a strong immune response, is limited. Therefore, to enhance binding to MHC and improve immune responses, anchor modifications of non-canonical tumour-associated peptides would be advantageous. In this study, the non-canonical tumour-associated peptide from MUC1, MUC1-8 (SAPDTRPA), was modified at the MHC anchor residues to SAPDFRPL (MUC1-8-5F8L) and showed enhanced binding to H-2Kb and improved immune responses. Furthermore, the crystal structure of MUC1-8-5F8L in complex with H-2Kb was determined and it revealed that binding of the peptide to MHC is similar to that of the canonical peptide OVA8 (SIINFEKL). Enhanced major histocompatibility complex class I binding and immune responses through anchor modification of the non-canonical tumour-associated mucin 1-8 peptide.,Lazoura E, Lodding J, Farrugia W, Ramsland PA, Stevens J, Wilson IA, Pietersz GA, Apostolopoulos V Immunology. 2006 Nov;119(3):306-16. PMID:17067310[19] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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