6o9b
Crystal structure of HLA-A3*01 in complex with a wild-type beta-catenin peptide
Structural highlights
DiseaseCTNB1_HUMAN Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM:114500. Note=Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life. Defects in CTNNB1 are a cause of pilomatrixoma (PTR) [MIM:132600; a common benign skin tumor.[1] [2] [3] Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:155255. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[4] [5] Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1. Defects in CTNNB1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.[6] FunctionCTNB1_HUMAN Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.[7] [8] [9] [10] Publication Abstract from PubMedMutations in CTNNB1, the gene encoding beta-catenin, are common in colon and liver cancers, the most frequent mutation affecting Ser-45 in beta-catenin. Peptides derived from wild-type beta-catenin have previously been shown to be presented on the cell surface as part of Major Histocompatibility Complex (MHC) Class I, suggesting an opportunity for targeting this common driver gene mutation with antibody-based therapies. Here, crystal structures of both the wild-type and S45F mutant peptide bound to HLA-A*03:01 at 2.20 and 2.45 A resolutions, respectively, confirmed the accessibility of the phenylalanine residue for antibody recognition. Phage display was then used to identify single chain variable fragment clones that selectively bind the S45F mutant peptide presented in HLA-A*03:01 and have minimal wild-type or other off-target binding. Following initial characterization of five clones, we selected a single clone, E10, for further investigation. We developed a computational model of the binding of E10 to the mutant peptide bound HLA-A3, incorporating data from affinity maturation as initial validation. In the future, our model may be used to design clones with maintained specificity and higher affinity. Such derivatives could be adapted into either cell-based (CAR-T) or protein-based (bispecific T-cell engagers) therapies to target cancer cells harboring the S45F mutation in CTNNB1. An engineered antibody fragment targeting mutant beta-catenin via Major Histocompatibility Complex I neoantigen presentation.,Miller MS, Douglass J, Hwang MS, Skora AD, Murphy M, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB J Biol Chem. 2019 Nov 5. pii: RA119.010251. doi: 10.1074/jbc.RA119.010251. PMID:31690625[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
