Drosophila melanogaster Guk-holder and Scribbled PDZ1 domain and Scribbled and Discs Large.pdf (3.51 MB)
Drosophila melanogaster Guk-holder interacts with the Scribbled PDZ1 domain and regulates epithelial development with Scribbled and Discs Large
journal contributionposted on 29.01.2021, 03:40 by Sofia Caria, Charlene Magtoto, Tinaz Samiei, Marta Portela-Esteban, Krystle Lim, Jing Yuan How, Bryce Stewart, Patrick Humbert, Helena Richardson, Marc Kvansakul
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Epithelial cell polarity is controlled by components of the Scribble polarity module, and its regulation is critical for tissue architecture and cell proliferation and migration. In Drosophila melanogaster, the adaptor protein Guk-holder (Gukh) binds to the Scribbled (Scrib) and Discs Large (Dlg) components of the Scribble polarity module and plays an important role in the formation of neuromuscular junctions. However, Gukh’s role in epithelial tissue formation and the molecular basis for the Scrib–Gukh interaction remain to be defined. We now show using isothermal titration calorimetry that the Scrib PDZ1 domain is the major site for an interaction with Gukh. Furthermore, we defined the structural basis of this interaction by determining the crystal structure of the Scrib PDZ1–Gukh complex. The C-terminal PDZ-binding motif of Gukh is located in the canonical ligand-binding groove of Scrib PDZ1 and utilizes an unusually extensive network of hydrogen bonds and ionic interactions to enable binding to PDZ1 with high affinity. We next examined the role of Gukh along with those of Scrib and Dlg in Drosophila epithelial tissues and found that Gukh is expressed in larval-wing and eye-epithelial tissues and co-localizes with Scrib and Dlg at the apical cell cortex. Importantly, we show that Gukh functions with Scrib and Dlg in the development of Drosophila epithelial tissues, with depletion of Gukh enhancing the eye- and wing-tissue defects caused by Scrib or Dlg depletion. Overall, our findings reveal that Scrib’s PDZ1 domain functions in the interaction with Gukh and that the Scrib–Gukh interaction has a key role in epithelial tissue development in Drosophila.
JournalJournal of Biological Chemistry
Pagination13p. (p. 4519-4531)
PublisherAmerican Society for Biochemistry and Molecular Biology
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyNANCE-HORAN-SYNDROMECELL POLARITYSUPERTERTIARY STRUCTURELIGAND SPECIFICITYSYNDROME PROTEINCOMPLEXGENELGLPROLIFERATIONMIGRATIONEyeEpithelial CellsAnimalsDrosophila melanogasterDrosophila ProteinsTumor Suppressor ProteinsNerve Tissue ProteinsCell PolarityGene Expression Regulation, DevelopmentalProtein BindingFemaleMalePDZ DomainsWings, AnimalDrosophilaX-ray crystallographycell polaritydrosophila geneticsgukholderisothermal titration calorimetry (ITC)scribbleMembrane Proteins