E6 - protein

The E6 protein is one of the key cancer-causing proteins expressed by the Human papillomavirus (HPV). Among the strains of HPV known to cause physical changes associated with cancer and pre-cancerous lesions, three oncoproteins are recognized: E5, E6 and E7. Although low-risk HPV strains also produce these proteins, the four major high-risk strains—HPV-16, HPV-18, HPV-31, and HPV-45—all exhibit E6 and E7 proteins.^[1] E6's activity in the high-risk strains can be oncogenic, or cancer-promoting. Therefor, it is the strains which exhibit these proteins which are associated with cervical cancer and pre-cancerous lesion development in women.

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Structure of E6

E6 is a 151 amino-acid peptide that incorporates a type 1 motif with a consensus sequence –(T/S)-(X)-(V/I)-COOH.^[1][2] It also has two zinc finger motifs.^[1]

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E6 is of particular interest because it appears to have multiple roles in the cell and to interact with many other proteins. E6 primarily causes cancer by associating with and thereby inactivating P53 or Rb proteins, which act as tumor suppressors. When tumor suppressor proteins are inactivated tumor growth proceeds unchecked. E6's interaction with p53 and Rb marks these proteins for degradation by ubiquitylation and ubiquitin ligase.^[3][4] E6 is proven to act on other cellular proteins, and to positively affect telomerase activity, thus inactivating one of the ways by which cells are normally prevented from dividing unchecked.^[5] Additionally, E6 can act as a transcriptional cofactor—specifically, a transcription activator—when interacting with the cellular transcription factor, E2F1/DP1.^[1]

E6 can also bind to PDZ-domains, short sequences which are often found in signalling proteins. E6's structural motif allows for interaction with PDZ domains on DLG (discs large) and hDLG (Drosophila large) tumor suppressor genes.^[6][2] Binding at these locations causes transformation of the DLG protein and disruption of its suppressor function. E6 proteins also interact with the MAGUK (membrane-associated guanylate kinase family) proteins. These proteins, including MAGI-1, MAGI-2, and MAGI-3 are usually structural proteins, and can help with signaling.^[2][6] More significantly, they are believed to be involved with DLG's suppression activity. When E6 complexes with the PDZ domains on the MAGI proteins, it distorts their shape and thereby impedes their function. Overall, the E6 protein serves to impede normal protein activity in such a way as to allow a cell to grow and multiply at the increased rate characteristic of cancer.

Footnotes

1. ^ ^{a b c d} Gupta S, Takhar PP, Degenkolbe R, Koh CH, Zimmermann H, Yang CM, Guan Sim K, Hsu SI, Bernard HU (2003). "The human papillomavirus type 11 and 16 E6 proteins modulate the cell-cycle regulator and transcription cofactor TRIP-Br1". Virology 317 (1): 155-64. PMID 14675634.
2. ^ ^{a b c} Glaunsinger BA, Lee SS, Thomas M, Banks L, Javier R (2000). "Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins". Oncogene 19 (46): 5270-80. PMID 11077444.
3. ^ iHOP information Hyperlinked over Proteins UBE3A. Retrieved on 2007-05-01.
4. ^ Biochemistry, Nottingham University - 3.0 Enzymes of the Ubiquitin Pathway. Retrieved on 2007-05-01.
5. ^ Kelley ML, Keiger KE, Lee CJ, Huibregtse JM (2005). "The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase". J. Virol. 79 (6): 3737-47. PMID 15731267.
6. ^ ^{a b} Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T, Ishibashi M (1997). "Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein". Proc. Natl. Acad. Sci. U.S.A. 94 (21): 11612-6. PMID 9326658.