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Structural insight into the Scribble PDZ domains interaction with the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax1 PBM

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Scribble (Scrib) is a highly conserved cell polarity regulator that harbours potent tumour suppressor activity and plays an important role in cell migration. Dysregulation of polarity is associated with poor prognosis during viral infections. Human T-cell lymphotrophic virus-1 (HTLV-1) encodes for the oncogenic Tax1 protein, a modulator of the transcription of viral and human proteins that can cause cell cycle dysregulation as well as a loss of genomic integrity. Previous studies established that Scribble interacts with Tax1 via its C-terminal PDZ-binding motif (PBM), leading to aggregation of polarity regulators and subsequent perturbation of host cell adhesion, proliferation, and signalling. Using isothermal titration calorimetry, we now show that all four PDZ domains of Scribble bind to Tax1 PBM. We then determined crystal structures of Scribble PDZ1, PDZ2 and PDZ3 domains bound to Tax1 PBM. Our findings establish a structural basis for Tax1-mediated subversion of Scribble-mediated cell polarity signalling and provide the platform for mechanistic studies to examine Tax1 induced mislocalization of Scribble and the associated changes in cellular architecture and subsequent tumorigenesis.

Funding

We thank the staff at the MX beamlines at the Australian Synchrotron for help with X-ray data collection. We thank the ACRF for their support of the Eiger MX detector at the Australian Synchrotron MX2 beamline and the Comprehensive Proteomics Platform at La Trobe University for core instrument support. This research was funded by the Australian Research Council (Fellowship FT130101349 to MK), National Health and Medical Research Council of Australia (Project Grant APP1007918 to MK and POH), La Trobe University (Scholarships to AJJ, JCM and ERRM). ERRM is the recipient of a Grains Research and Development Corporation scholarship (grant no. 9176977). Open access publishing facilitated by La Trobe University, as part of the Wiley - La Trobe University agreement via the Council of Australian University Librarians.

History

Publication Date

2023-02-01

Journal

The FEBS Journal

Volume

290

Issue

4

Pagination

14p. (p. 974-987)

Publisher

John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

ISSN

1742-464X

Rights Statement

© 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.