# ASPPs multimerize protein phosphatase 1

## TL;DR

ASPP proteins help organize protein phosphatase 1 (PP1) into clusters at cell junctions, and this organization is crucial for proper cell function.

## Contribution

ASPPs multimerize PP1 to form concentrated phosphatase hubs, a previously unknown regulatory mechanism.

## Key findings

- ASPPs bind superstoichiometric amounts of PP1, promoting higher-order PP1 assemblies.
- Missense mutations in ASPPs reduce PP1 binding stoichiometry and disrupt development in C. elegans.
- Forcing PP1 oligomerization rescues mutant ASPP function in vivo.

## Abstract

Protein Phosphatase 1 (PP1) activity is thought to be spatiotemporally defined by hundreds of different regulatory subunits, but their mechanisms of action are largely unknown. The Ankyrin repeat, SH3-domain, and Proline-rich region containing Proteins (ASPPs) bind and localize PP1 to cell-cell junctions. Here, we show ASPPs bind superstoichiometric amounts of PP1. Missense mutations in the ankyrin repeats of ASPPs, that were previously isolated from a forward genetic screen in Caenorhabditis elegans, reduce the stoichiometry of PP1 binding. Forcing PP1 oligomerization restores mutant ASPP function in vivo. We propose that ASPPs multimerize PP1 to establish a concentrated hub of phosphatase activity at cell-cell junctions.

We have elucidated a new mechanism governing protein phosphatase 1 (PP1) activity. A family of proteins called the ASPPs function to spatially regulate PP1 by recruiting active phosphatase to specific subcellular locations. Critically, we observed that ASPPs promote the formation of higher-order PP1 assemblies – a previously unrecognized regulatory mechanism. We identified specific ASPP mutants in our nematode model organism that disrupt PP1 oligomerization, leading to altered development. However, inducing PP1 clustering was sufficient to rescue these ASPP mutants, underscoring the functional significance of ASPP-mediated PP1 oligomerization. These results provide new insights into the intricate control of cellular signaling pathways mediated by PP1 and may have implications for understanding diseases associated with dysregulated phosphatase activity.