PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch

Area of Science:

• Cellular signaling
• Protein biochemistry
• Molecular biology

Background:

• Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylarginine deposition in mammalian cells.
• PRMT5 regulation is key to understanding its cellular functions.
• A threonine phosphorylation site on PRMT5's C-terminal tail is targeted by Akt/serum- and glucocorticoid-inducible kinases.

Purpose of the Study:

• To investigate the function of PRMT5 C-terminal tail phosphorylation.
• To explore the prevalence of PDZ/14-3-3 interaction switching in signal transduction.
• To identify other mammalian proteins utilizing this signaling mechanism.

Main Methods:

• Identification of a threonine phosphorylation site on PRMT5.
• Characterization of PRMT5 C-terminal tail interactions with PDZ and 14-3-3 proteins.
• Development and application of a protein domain microarray harboring PDZ domains and 14-3-3 proteins.
• Interrogation of candidate protein C-terminal tails using the microarray.

Main Results:

• PRMT5's C-terminal tail exhibits a phosphorylation-dependent switch, binding PDZ domains when unphosphorylated and 14-3-3 proteins when phosphorylated.
• This PDZ/14-3-3 switching is essential for PRMT5's plasma membrane association and organismal survival.
• The signaling switch mechanism was identified in ERBB4, PGHS2, and IRK1, in addition to PRMT5 and HPV E6.

Conclusions:

• A novel posttranslational modification-dependent interaction switch involving PDZ and 14-3-3 proteins regulates PRMT5.
• This PDZ/14-3-3 switching mechanism appears to be a widespread biological paradigm in signal transduction.
• Further research into this signaling mode could reveal new therapeutic targets.