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. We have investigated the structural basis for two different mechanisms of viral disruptions by IDPs from Human Papilloma virus (HPV) and from the human T-cell leukemia virus (HTLV-1). The intrinsically disordered HPV E7 protein interacts with two major cellular control proteins, the retinoblastoma protein pRb and the CREB-binding protein CBP and forms a ternary complex with the pRb pocket domain and the TAZ2 domain of CBP. Oncogenic potential of high- and low-risk HPV strains appears to be related to strain-specific affinity differences of the E7 protein for the TAZ2 domain and for pRb. A different mechanism appears to be employed by the human T-cell leukemia virus (HTLV-1). Chronic viral infection and leukemia are promoted through the actions of its basic leucine zipper protein HBZ. The intrinsically disordered N-terminal activation domain of HBZ binds to the KIX domain of CBP, competing directly with cellular and viral transcription factors for binding to one of the two distinct sites on KIX. A ternary complex between KIX, HBZ and the hematopoietic transcription factor c-Myb provides an example of cooperative stabilization in a transcription factor-coactivator network, and may provide insights into the means whereby HBZ dysregulates hematopoietic transcriptional programs and promotes T-cell proliferation.

Disordered viral proteins

ACS Spring 2022

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