The interaction between human papillomavirus type 16 and FADD is mediated by a novel E6 binding domain.
High-risk strains of human papillomavirus, such as types 16 and 18, have been etiologically linked to cervical cancer. Most cervical cancer tissues are positive for both the E6 and E7 oncoproteins, since it is their cooperation that results in successful transformation and immortalization of infected cells. We have reported that E6 binds to tumor necrosis factor receptor 1 and to Fas-associated death domain (FADD) and, in doing so, prevents E6-expressing cells from responding to apoptotic stimuli. The binding site of E6 to FADD localizes to the first 23 amino acids of FADD and has now been further characterized by the use of deletion and site-directed mutants of FADD in pull-down and functional assays. The results from these experiments revealed that mutations of serine 16, serine 18, and leucine 20 obstruct FADD binding to E6, suggesting that these residues are part of the E6 binding domain on FADD. Because FADD does not contain the two previously identified E6 binding motifs, the LxxphiLsh motif, and the PDZ motif, a novel binding domain for E6 has been identified on FADD. Furthermore, peptides that correspond to this region can block E6/FADD binding in vitro and can resensitize E6-expressing cells to apoptotic stimuli in vivo. These results demonstrate the existence of a novel E6 binding domain.
Tungteakkhun
Sandy S
SS
Department of Basic Sciences, Loma Linda University School of Medicine, 11085 Campus Street, 121 Mortensen Hall, Loma Linda, CA 92354, USA.
Filippova
Maria
M
Neidigh
Jonathan W
JW
Fodor
Nadja
N
Duerksen-Hughes
Penelope J
PJ
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005260:Female; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000628:therapy / Q000821:virology
D053200:Fas-Associated Death Domain Protein; D047888:Receptors, Tumor Necrosis Factor, Type I; D016159:Tumor Suppressor Protein p53