| 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
[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]
Publication Abstract from PubMed
SEA domains are ubiquitous in large proteins associated with highly glycosylated environments. Certain SEA domains undergo intramolecular proteolysis involving a nucleophilic attack of a serine hydroxyl group on the preceding glycine carbonyl. The mucin-1 (MUC1) SEA domain has been extensively investigated as a model of intramolecular proteolysis. Since neither a general base, a general acid, nor an oxyanion hole could be identified in MUC1 SEA, it has been suggested that proteolysis is accelerated by a non-planarity of the scissile peptide bond imposed by protein folding. A reactant distorted peptide bond has been also invoked to explain the autoproteolysis of several unrelated proteins. However, the only evidence of peptide distortion in MUC1 SEA stems from molecular dynamic simulations of the reactant modeled upon a single NMR structure of the cleaved product. We report the first high-resolution X-ray structure of cleaved MUC1 SEA. Structural comparison with uncleaved SEA domains suggests that the number of residues evolutionarily inserted in the cleaved loop of MUC1 SEA precludes the formation of a properly hydrogen-bonded beta turn. By sequence analysis, we show that this conformational frustration is shared by all known cleaved SEA domains. In addition, alternative conformations of the uncleaved precursor could be modeled in which the scissile peptide bond is planar. The implications of these structures for autoproteolysis are discussed in the light of the previous research on autoproteolysis.
High-resolution structure of intramolecularly proteolyzed human mucin-1 SEA domain.,Noguera ME, Jakoncic J, Ermacora MR Biochim Biophys Acta Proteins Proteom. 2020 Mar;1868(3):140361. doi:, 10.1016/j.bbapap.2020.140361. Epub 2020 Jan 7. PMID:31923589[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem. 1997 May 9;272(19):12492-4. PMID:9139698
- ↑ Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002 May 17;277(20):17616-22. Epub 2002 Mar 4. PMID:11877440 doi:10.1074/jbc.M200436200
- ↑ Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec;2(6):702-6. PMID:14688481
- ↑ Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005 Feb;7(2):167-78. PMID:15710329 doi:10.1016/j.ccr.2005.01.008
- ↑ Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15;65(22):10413-22. PMID:16288032 doi:65/22/10413
- ↑ Mukherjee P, Tinder TL, Basu GD, Gendler SJ. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol. 2005 Jan;77(1):90-9. Epub 2004 Oct 28. PMID:15513966 doi:jlb.0604333
- ↑ Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
- ↑ Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 2007 Feb 15;67(4):1853-8. PMID:17308127 doi:67/4/1853
- ↑ Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene. 2007 Mar 15;26(12):1693-701. Epub 2006 Sep 18. PMID:16983337 doi:1209976
- ↑ Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem. 1997 May 9;272(19):12492-4. PMID:9139698
- ↑ Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002 May 17;277(20):17616-22. Epub 2002 Mar 4. PMID:11877440 doi:10.1074/jbc.M200436200
- ↑ Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D. MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther. 2003 Nov-Dec;2(6):702-6. PMID:14688481
- ↑ Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005 Feb;7(2):167-78. PMID:15710329 doi:10.1016/j.ccr.2005.01.008
- ↑ Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res. 2005 Nov 15;65(22):10413-22. PMID:16288032 doi:65/22/10413
- ↑ Mukherjee P, Tinder TL, Basu GD, Gendler SJ. MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol. 2005 Jan;77(1):90-9. Epub 2004 Oct 28. PMID:15513966 doi:jlb.0604333
- ↑ Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
- ↑ Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 2007 Feb 15;67(4):1853-8. PMID:17308127 doi:67/4/1853
- ↑ Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene. 2007 Mar 15;26(12):1693-701. Epub 2006 Sep 18. PMID:16983337 doi:1209976
- ↑ Noguera ME, Jakoncic J, Ermacora MR. High-resolution structure of intramolecularly proteolyzed human mucin-1 SEA domain. Biochim Biophys Acta Proteins Proteom. 2020 Mar;1868(3):140361. doi:, 10.1016/j.bbapap.2020.140361. Epub 2020 Jan 7. PMID:31923589 doi:http://dx.doi.org/10.1016/j.bbapap.2020.140361
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