Pin1-Mediated Protein Kinase C Regulation Mechanism Revealed

Kernekoncepter

Pin1 regulates PKCα and PKCβII stability through a non-catalytic bivalent interaction mode, contrary to previous beliefs.

Resumé

The study reveals a novel mechanism of Pin1-mediated regulation of PKC isoforms. Pin1 acts as a binding partner, sequestering phosphorylated motifs in the C-terminal tail of PKC. The structural analysis shows a bivalent interaction mode between Pin1 and the C-terminal tail of PKCβII. This non-catalytic mechanism represents an unappreciated mode of regulation for AGC kinases. The findings challenge the conventional model of Pin1 action on PKCs, shedding light on new regulatory pathways.

Statistik

Regulated hydrolysis defines eukaryotic signaling pathways.
Proteasome-dependent degradation pathway downregulates stimulated PKC activity.
Pin1 does not catalyze cis-trans isomerization of pThr-Pro motifs in PKCs.
Pin1 interacts with both WW and PPIase domains in a bivalent manner.

Citater

"Pin1's role in regulating conventional PKCs is non-catalytic but involves sequestration of key kinase motifs."
"Structural analysis reveals a unique bivalent interaction mode between Pin1 and the C-terminal tail of PKCβII."

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A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated Protein Kinase C regulation

by Chen,X.-R., ... kl. www.biorxiv.org 09-20-2023

https://www.biorxiv.org/content/10.1101/2023.09.18.558341v2

Dybere Forespørgsler

How might the discovery of a non-catalytic role for Pin1 impact future research on protein kinase regulation?

The discovery of a non-catalytic role for Pin1 in regulating protein kinases, such as PKCα and PKCβII, opens up new avenues for research in the field of protein kinase regulation. This finding challenges the traditional understanding that Pin1 functions solely as a prolyl isomerase and highlights its ability to regulate substrate activity through bivalent interactions. Future research may focus on elucidating similar non-catalytic roles for Pin1 in other substrates and signaling pathways. Understanding these alternative mechanisms can provide deeper insights into how cellular processes are regulated beyond conventional enzymatic activities.

What implications could this novel bivalent interaction mode have for developing targeted therapies?

The novel bivalent interaction mode between Pin1 and PKC isoforms presents exciting opportunities for developing targeted therapies. By targeting specific regions involved in this unique binding mechanism, researchers could potentially design small molecules or peptides that disrupt or enhance these interactions selectively. Such targeted therapies could modulate the stability and activity of key enzymes like PKCs implicated in various diseases including cancer, cardiovascular disorders, diabetes, and neurodegenerative conditions. Additionally, understanding this interaction mode may lead to the development of more effective inhibitors or activators with improved specificity and efficacy compared to current approaches.

How does understanding the mechanisms behind Pin1-mediated regulation contribute to our broader knowledge of cellular signaling pathways?

Understanding the intricate mechanisms by which Pin1 regulates proteins like PKCs contributes significantly to our broader knowledge of cellular signaling pathways. It sheds light on complex regulatory networks within cells where post-translational modifications play crucial roles in signal transduction cascades. The identification of a non-catalytic function for Pin1 underscores the versatility of regulatory proteins in modulating cellular responses beyond their canonical enzymatic activities. This knowledge enhances our comprehension of how cells integrate external cues into intracellular signaling events through precise molecular interactions involving key regulators like Pin1. Ultimately, unraveling these mechanisms provides valuable insights into disease pathogenesis and offers potential targets for therapeutic interventions aimed at restoring normal cell function.