Phosphorylation-induced changes in the PDZ domain of Dishevelled 3

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Publikace nespadá pod Lékařskou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

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JURÁSEK Miroslav KUMAR Jitender PACLÍKOVÁ Petra JADAUN Alka Kumari TRIPSIANES Konstantinos BRYJA Vítězslav VÁCHA Robert

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj Scientific Reports
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.nature.com/articles/s41598-020-79398-5
Doi http://dx.doi.org/10.1038/s41598-020-79398-5
Klíčová slova HUMAN PHOSPHATASE HPTP1E; PARTICLE MESH EWALD; PROTEIN INTERACTIONS; LIGAND RECOGNITION; PAR-6 PDZ; BINDING; DYNAMICS; REVEALS; COMPLEX; MODES
Popis The PDZ domain of Dishevelled 3 protein belongs to a highly abundant protein recognition motif which typically binds short C-terminal peptides. The affinity of the PDZ towards the peptides could be fine-tuned by a variety of post-translation modifications including phosphorylation. However, how phosphorylations affect the PDZ structure and its interactions with ligands remains elusive. Combining molecular dynamics simulations, NMR titration, and biological experiments, we explored the role of previously reported phosphorylation sites and their mimetics in the Dishevelled PDZ domain. Our observations suggest three major roles for phosphorylations: (1) acting as an on/off PDZ binding switch, (2) allosterically affecting the binding groove, and (3) influencing the secondary binding site. Our simulations indicated that mimetics had similar but weaker effects, and the effects of distinct sites were non-additive. This study provides insight into the Dishevelled regulation by PDZ phosphorylation. Furthermore, the observed effects could be used to elucidate the regulation mechanisms in other PDZ domains.
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