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


ABSTRACT: Polyglutamylation is a reversible post-translational 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 non-canonical 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 first evidence that polyglutamylation can modulate protein phase separation.

SUBMITTER: Dr. Marek Kravec 

PROVIDER: S-SCDT-10_1038-S44318-024-00254-7 | biostudies-other |

REPOSITORIES: biostudies-other

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