Poster Presentation The 45th Lorne Conference on Protein Structure and Function 2020

Structural biology of the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax protein subversion on the Scribble cell polarity module. (#121)

Airah Javorsky 1 , Patrick Humbert 1 , Mark Hulett 1 , Marc Kvansakul 1
  1. La Trobe University, Rosanna, VIC, Australia

The scribble cell polarity module consists of Disc-large (Dlg), Lethal-2-giant larvae (Lgl) and Scribble (Scrib). It harbours potent anti-proliferative properties due to their regulation of cell spatial orientation. Deregulation of polarity is associated with poor prognosis in viral infections due to interference with Scribble PDZ domains that differentially regulate the interaction network and appropriate localisation. Previous studies have established that Scribble interacts with the HTLV-1 Tax protein through its C-terminal PDZ binding motif (PBM), causing aggregation of polarity regulators and consequently, these interactions disturb the host’s ability to control cell adhesion, proliferation, and signalling. A study conducted in humanized CD34+ mice demonstrated that Tax PBM enhances HTLV-1-induced T-cell proliferation. Isothermal titration calorimetry (ITC) shows that tax binds to all the PDZ domains of Scribble with entropy-driven interactions consisting of hydrogen bonding. This finding was further supported with the Scribble PDZ3 and tax PBM crystal complex. The mislocalisation of scribble upon binding of Tax PBM potentially is the link to the morphological changes that affect the cellular architecture and help the sustained cellular proliferation leading to tumorigenesis.

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