Carboxy-terminal polyglutamylation regulates signaling and phase separation of the Dishevelled protein

. 2024 Nov ; 43 (22) : 5635-5666. [epub] 20240930

Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid39349846

Grantová podpora
GX19-28347X Czech Science Foundation
GA22-25365S Czech Science Foundation
GA23-07149S Czech Science Foundation
GA22-06405S Czech Science Foundation
ANR-10-IDEX-0001-02 Agence Nationale de la Recherche (ANR)
ANR-12-BSV2-0007 Agence Nationale de la Recherche (ANR)
ANR-17-CE13-0021 Agence Nationale de la Recherche (ANR)
ANR-11-LBX-0038 LabEx Cell&Scale grant
ANR-17-CONV-0005 Institut de convergence Q-life grant
86652036 Czech Academy of Sciences grant RVO
1414120 Charles University Grant Agency
LM2018129 MEYS CR
LM2018127 MEYS CR
CZ.02.1.01/0.0/0.0/18_046/0015974 European Regional Development Fund-Project
INFRA LM2018140 e-Infrastruktura CZ
LX22NPO5102 Funded by the European Union - Next Generation EU - National Institute for Cancer Research

Odkazy

PubMed 39349846
PubMed Central PMC11574253
DOI 10.1038/s44318-024-00254-7
PII: 10.1038/s44318-024-00254-7
Knihovny.cz E-zdroje

Polyglutamylation is a reversible posttranslational modification that is catalyzed by enzymes of the tubulin tyrosine ligase-like (TTLL) family. Here, we found that TTLL11 generates a previously unknown type of polyglutamylation that is initiated by the addition of a glutamate residue to the free C-terminal carboxyl group of a substrate protein. TTLL11 efficiently polyglutamylates the Wnt signaling protein Dishevelled 3 (DVL3), thereby changing the interactome of DVL3. Polyglutamylation increases the capacity of DVL3 to get phosphorylated, to undergo phase separation, and to act in the noncanonical Wnt pathway. Both carboxy-terminal polyglutamylation and the resulting reduction in phase separation capacity of DVL3 can be reverted by the deglutamylating enzyme CCP6, demonstrating a causal relationship between TTLL11-mediated polyglutamylation and phase separation. Thus, C-terminal polyglutamylation represents a new type of posttranslational modification, broadening the range of proteins that can be modified by polyglutamylation and providing the first evidence that polyglutamylation can modulate protein phase separation.

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