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bioRxiv · 10.1101/2022.02.15.480428

The C. elegans ASPP homolog APE-1 is a junctional protein phosphatase 1 modulator

Beacham, G. M.·Wei, D. T.·Beyrent, E.·Zhang, Y.·Zheng, J.·Camacho, M. M. K.·Florens, L.·Hollopeter, G.
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Abstract

How serine/threonine phosphatases are spatially and temporally tuned by regulatory subunits is a fundamental question in cell biology. Ankyrin repeat, SH3 domain, proline-rich-region-containing proteins (ASPPs) are protein phosphatase 1 (PP1) binding partners associated with cardiocutaneous diseases. ASPPs localize PP1 to cell-cell junctions, but how ASPPs localize and whether they regulate PP1 activity in vivo is unclear. Through a C. elegans genetic screen, we find that loss of the ASPP homolog, APE-1, suppresses a pathology called jowls, providing us with an in vivo assay for APE-1 activity. Using structure-function analysis, we discover that APE-1s N-terminal half directs the APE-1-PP1 complex to intercellular junctions. Additionally, we isolated mutations in highly conserved residues of APE-1s ankyrin repeats that suppress jowls yet do not preclude PP1 binding, implying ASPPs do more than simply localize PP1. Indeed, in vivo reconstitution of APE-1 suggests the ankyrin repeats modulate phosphatase output, a function we find to be conserved among vertebrate homologs.

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Beacham, G. M., Wei, D. T., Beyrent, E., Zhang, Y., Zheng, J., Camacho, M. M. K., Florens, L., Hollopeter, G.. 2022-02-18. The C. elegans ASPP homolog APE-1 is a junctional protein phosphatase 1 modulator. https://doi.org/10.1101/2022.02.15.480428

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