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Journal Articles Biochemical Journal Year : 2015

Deciphering the unconventional peptide binding to the PDZ domain of MAST2

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Abstract

Phosphatase and tensin homologue (PTEN) and microtubule-associated serine threonine kinase 2 (MAST2) are key negative regulators of survival pathways in neuronal cells. The two proteins interact via the PDZ (PSD-95, Dlg1, Zo-1) domain of MAST2 (MAST2-PDZ). During infection by rabies virus, the viral glycoprotein competes with PTEN for interaction with MAST2-PDZ and promotes neuronal survival. The C-terminal PDZ-binding motifs (PBMs) of the two proteins bind similarly to MAST2-PDZ through an unconventional network of connectivity involving two anchor points. Combining stopped-flow fluorescence, analytical ultracentrifugation (AUC), microcalorimetry and NMR, we document the kinetics of interaction between endogenous and viral ligands to MAST2-PDZ as well as the dynamic and structural effects of these interactions. Viral and PTEN peptide interactions to MAST2-PDZ occur via a unique kinetic step which involves both canonical C-terminal PBM binding and N-terminal anchoring. Indirect effects induced by the PBM binding include modifications to the structure and dynamics of the PDZ dimerization surface which prevent MAST2-PDZ auto-association. Such an energetic communication between binding sites and distal surfaces in PDZ domains provides interesting clues for protein regulation overall.
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Dates and versions

pasteur-02883950 , version 1 (29-06-2020)

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Florent Delhommel, Alain Chaffotte, Elouan Terrien, Bertrand Raynal, Henri Buc, et al.. Deciphering the unconventional peptide binding to the PDZ domain of MAST2. Biochemical Journal, 2015, 469 (1), pp.159-168. ⟨10.1042/BJ20141198⟩. ⟨pasteur-02883950⟩
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