Abstract
The tumor suppressors Discs Large (Dlg), Lethal giant larvae (Lgl) and Scribble are essential for the establishment and maintenance of epithelial cell polarity in metazoan. Dlg, Lgl and Scribble are known to interact strongly with each other genetically and form the evolutionarily conserved Scribble complex. Despite more than a decade of extensive research, it has not been demonstrated whether Dlg, Lgl and Scribble physically interact with each other. Here, we show that Dlg directly interacts with Lgl in a phosphorylation-dependent manner. Phosphorylation of any one of the three conserved Ser residues situated in the central linker region of Lgl is sufficient for its binding to the Dlg guanylate kinase (GK) domain. The crystal structures of the Dlg4 GK domain in complex with two phosphor-Lgl2 peptides reveal the molecular mechanism underlying the specific and phosphorylation-dependent Dlg/Lgl complex formation. In addition to providing a mechanistic basis underlying the regulated formation of the Scribble complex, the structure of the Dlg/Lgl complex may also serve as a starting point for designing specific Dlg inhibitors for targeting the Scribble complex formation.
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Acknowledgements
We thank Shanghai Synchrotron Radiation Facility (SSRF) BL17U for X-ray beam time. This work was supported by grants from RGC of Hong Kong (663610, 663811, 663812, HKUST6/CRF/10, SEG_HKUST06, AoE/M09/12 and T13-607/12R) to MZ and National Institute of Health (GM079506) to QD. MZ is a Kerry Holdings Professor in Science and a Senior Fellow of IAS at HKUST.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Dlg1 SH3-GK binds to Lgl2 in a phosphorylation dependent manner. (PDF 91 kb)
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Zhu, J., Shang, Y., Wan, Q. et al. Phosphorylation-dependent interaction between tumor suppressors Dlg and Lgl. Cell Res 24, 451–463 (2014). https://doi.org/10.1038/cr.2014.16
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DOI: https://doi.org/10.1038/cr.2014.16
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