Structural analysis of phosphorylation‐associated interactions of human MCC with Scribble PDZ domains
| Autor: | Ruitao Jin, Marc Kvansakul, Patrick O. Humbert, Sofia Caria, Brian J. Smith, Bryce Z. Stewart |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Tissue architecture PDZ domain PDZ Domains Calorimetry Molecular Dynamics Simulation Crystallography X-Ray Biochemistry Protein Structure Secondary 03 medical and health sciences 0302 clinical medicine Cell polarity Humans Phosphorylation Cell adhesion Molecular Biology Scribble Binding Sites Chemistry Tumor Suppressor Proteins Membrane Proteins food and beverages Signal transducing adaptor protein Cell migration Cell Biology Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Peptides Protein Binding |
| Zdroj: | The FEBS Journal. 286:4910-4925 |
| ISSN: | 1742-4658 1742-464X |
| Popis: | Scribble is a crucial adaptor protein that plays a pivotal role during establishment and control of cell polarity, impacting many physiological processes ranging from cell migration to immunity and organization of tissue architecture. Scribble harbours a leucine-rich repeat domain and four PDZ domains that mediate most of Scribble's interactions with other proteins. It has become increasingly clear that post-translational modifications substantially impact Scribble-ligand interactions, with phosphorylation being a major modulator of binding to Scribble. To better understand how Scribble PDZ domains direct cell polarity signalling and how phosphorylation impacts this process, we investigated human Scribble interactions with MCC (Mutated in Colorectal Cancer). We systematically evaluated the ability of all four individual Scribble PDZ domains to bind the PDZ-binding motif (PBM) of MCC as well as MCC phosphorylated at the -1 Ser position. We show that Scribble PDZ1 and PDZ3 are the major interactors with MCC, and that modifications to Ser at the -1 position in the MCC PBM only has a minor effect on binding to Scribble PDZ domains. We then examined the structural basis for these observations by determining the crystal structures of Scribble PDZ1 domain bound to both the unphosphorylated MCC PBM as well as phosphorylated MCC. Our structures indicated that phospho-Ser at the -1 position in MCC is not involved in major contacts with Scribble PDZ1, and in conjunction with our affinity measurements suggest that the impact of phosphorylation at the -1 position of MCC must extend beyond a simple modulation of the affinity for Scribble PDZ domains. |
| Databáze: | OpenAIRE |
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