How do intrinsically disordered viral proteins hijack the cell?

Abstract

Intrinsically disordered viral proteins are central to the infectivity and pathogenicity of viruses. For oncogenic viruses, the presence of disordered proteins coded by the viral genome is an important part of the process of disruption of the host cell cycle that leads to cellular transformation. The human papillomavirus (HPV) is a DNA virus that infects cells of the skin and mucous membranes. The infections are mostly benign, resulting in the formation of papillomas (warts), but infection with certain strains causes a high risk of transformation to cancers, especially cervical cancer. High risk strains include HPV16, while HPV6 is a related strain with low risk of cancerous transformation. The proteins most implicated in the cancerous transformations mediated by HPV are E6 and E7. We studied the interactions of one of these proteins, E7, to elucidate the structural basis for the differences in cancer risk between high and low‐risk strains. The E7 protein interacts with two major cellular control proteins, the retinoblastoma protein pRb, which controls the entry of the cell into S phase of the cell cycle, halting the progression of cell division. pRb acts by sequestering the factor E2F which is required for cell cycle progression. The HPV E7 protein displaces E2F from pRb, initiating uncontrolled cellular proliferation. The other important interaction of E7 is with the CREB‐binding protein CBP, a transcriptional activator that mediates the transcription of p53‐related genes. The E7 protein disrupts p53 binding to CBP, abrogating the processes that lead to apoptosis of infected cells. Residues 1–51 of HPV E7 are intrinsically disordered and bind preferentially to the TAZ2 domain of CBP. Pull‐down assays show that a ternary E7‐pRb‐TAZ2 ternary complex is formed in the presence of full‐length E7(1–98). NMR chemical shift perturbation studies of TAZ2 in the presence of E7 and pRb demonstrate the formation of a ternary complex. The stability of the E7‐TAZ2‐pRb ternary complex probably holds an important clue to the oncogenic potential of the high‐risk HPV strains. A stable ternary complex will bring pRb into proximity to CBP, which contains in addition to the TAZ2 domain an acetyltransferase module that can acetylate pRb, leading to its degradation.Support or Funding InformationNIGMS GM113251This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.