Mancini, E. J. | bioRxiv Science

bioRxiv2021

Crosstalk between β-catenin and WT1 signalling activity in acute myeloid leukemia

Wnt signalling is an evolutionary conserved signal transduction pathway heavily implicated in normal development and disease. The central mediator of this pathway, {beta}-catenin, is frequently overexpressed, mislocalised and overactive in acute myeloid leukaemia (AML) where it mediates the establishment, maintenance and drug resistance of leukaemia stem cells. Critical to the stability, localisation and activity of {beta}-catenin are the protein-protein interactions it forms, yet these are poorly defined in AML. We recently performed the first {beta}-catenin interactome study in blood cells of any kind and identified a plethora of novel interacting partners. This study shows for the first time that {beta}-catenin interacts with Wilms tumour protein (WT1), a protein frequently overexpressed and mutated in AML, in both myeloid cell lines and also primary AML samples. We demonstrate crosstalk between the signalling activity of these two proteins in myeloid cells, and show that modulation of either protein can affect expression of the other. Finally, we demonstrate that WT1 mutations frequently observed in AML can increase stabilise {beta}-catenin and augment Wnt signalling output. This study has uncovered new context-dependent molecular interactions for {beta}-catenin which could inform future therapeutic strategies to target this dysregulated molecule in AML. Article summaryO_LI{beta}-Catenin is frequently dysregulated in acute myeloid leukemia (AML) and protein interactions govern its stability, localization and activity, but these are poorly defined in AML. C_LIO_LIThis study shows for the first time that {beta}-catenin and Wilms tumour protein (WT1) interact and influence each others expression level and signalling activity in AML cells, which could inform future therapeutic strategies. C_LI

cancer biology↗

bioRxiv2020

Structural Analysis of the PATZ1 BTB domain homodimer

PATZ1 is a transcriptional repressor belonging to the ZBTB family that is functionally expressed in T-lymphocytes, as well as in a ubiquitous fashion. PATZ1 targets the Cd8 gene in lymphocyte development and interacts with the p53 protein to control genes important in proliferation and DNA damage response. PATZ1 exerts its activity through an N-terminal BTB domain that mediates dimerization and co-repressor interactions and a C-terminal zinc finger motif-containing domain that mediates DNA binding. Here, the crystal structures of the murine and zebrafish PATZ1 BTB domains are reported at 2.3 and 1.8 [A] resolution respectively. The structures reveal that, like other ZBTB structures, the PATZ1 BTB domain forms a stable homodimer and likely binds co-repressors through a lateral surface groove that is formed upon dimerization. Analysis of the lateral groove reveals a large acidic patch in this region which contrasts previously resolved basic co-repressor binding interfaces in other ZBTB proteins. A large 30 amino acids glycine- and alanine-rich central loop, unique to mammalian PATZ1 amongst all ZBTB proteins, could not be resolved likely due to its flexibility. Modelling of this loop indicates that it can participate in the dimerization interface of BTB monomers. SynopsisThe crystal structures of the PATZ1 BTB domain in mammals and fish are homodimers. The core dimer conformation of these BTB proteins is dynamically stable, despite the presence of highly flexible regions in the dimerization interface.

molecular biology↗