Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein.
نویسندگان
چکیده
Human papillomavirus (HPV) E6 oncoprotein targets certain tumor suppressors such as MAGI-1 and SAP97/hDlg for degradation. A short peptide at the C terminus of E6 interacts specifically with the PDZ domains of these tumor suppressors, which is a property unique to high-risk HPVs that are associated with cervical cancer. The detailed recognition mechanisms between HPV E6 and PDZ proteins are unclear. To understand the specific binding of cellular PDZ substrates by HPV E6, we have solved the crystal structures of the complexes containing a peptide from HPV18 E6 bound to three PDZ domains from MAGI-1 and SAP97/Dlg. The complex crystal structures reveal novel features of PDZ peptide recognition that explain why high-risk HPV E6 can specifically target these cellular tumor suppressors for destruction. Moreover, a new peptide-binding loop on these PDZs is identified as interacting with the E6 peptide. Furthermore, we have identified an arginine residue, unique to high-risk HPV E6 but outside the canonical core PDZ recognition motif, that plays an important role in the binding of the PDZs of both MAGI-I and SAP97/Dlg, the mutation of which abolishes E6's ability to degrade the two proteins. Finally, we have identified a dimer form of MAGI-1 PDZ domain 1 in the cocrystal structure with E6 peptide, which may have functional relevance for MAGI-1 activity. In addition to its novel insights into the biochemistry of PDZ interactions, this study is important for understanding HPV-induced oncogenesis; this could provide a basis for developing antiviral and anticancer compounds.
منابع مشابه
Oncoprotein Suppressors by a High-Risk HPV Proteins: Mechanisms of Targeting Tumor (HPV) E6 Polypeptide Bound to MAGUK Structures of a Human Papillomavirus
متن کامل
Elucidating Molecular Interactions of Natural Inhibitors with HPV-16 E6 Oncoprotein through Docking Analysis
Human papillomavirus (HPV) infection is the leading cause of cancer mortality among women worldwide. The life-threatening infection caused by HPV demands the need for designing anticancerous drugs. In the recent years, different compounds from natural origins, such as carrageenan, curcumin, epigallocatechin gallate, indole-3-carbinol, jaceosidin, and withaferin, have been used as a hopeful sour...
متن کاملThe E6 oncoproteins of high-risk papillomaviruses bind to a novel putative GAP protein, E6TP1, and target it for degradation.
The high-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. Previous studies have identified two viral oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high-risk HPV E6 protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanism...
متن کاملInduction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein.
Certain types of human papillomaviruses (HPVs) are closely linked to the development of human cancers. Herein, it is shown that intracellular targeting of the HPV16 E6 oncoprotein by E6-binding peptide aptamers resulted in the apoptotic elimination of HPV16-positive cancer cells, whereas HPV-negative cells were not affected. These results provide direct experimental evidence that the HPV E6 onc...
متن کاملHuman Papillomavirus and Cancer - Immunological Consequences of MHC Class I Down-Regulation
Few studies have been conducted on the causative factors associated with the development of cancer. Infection by high risk human papillomaviruses (HPVs) have been implicated as causative agents in a variety of cancers. HPV is capable of evading immune system and establishing persistent infections. Prolonged infection and lesion maintenance are associated with higher risk of neoplastic progressi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Journal of virology
دوره 81 7 شماره
صفحات -
تاریخ انتشار 2007