ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail

M. Teresa Bertran, Stéphane Mouilleron (), Yanxiang Zhou, Rakhi Bajaj, Federico Uliana, Ganesan Senthil Kumar, Audrey Drogen, Rebecca Lee, Jennifer J. Banerjee, Simon Hauri, Nicola O’Reilly, Matthias Gstaiger, Rebecca Page, Wolfgang Peti and Nicolas Tapon ()
Additional contact information
M. Teresa Bertran: The Francis Crick Institute
Stéphane Mouilleron: The Francis Crick Institute
Yanxiang Zhou: The Francis Crick Institute
Rakhi Bajaj: University of Arizona
Federico Uliana: Institute of Molecular Systems Biology, ETH Zürich
Ganesan Senthil Kumar: University of Arizona
Audrey Drogen: Institute of Molecular Systems Biology, ETH Zürich
Rebecca Lee: The Francis Crick Institute
Jennifer J. Banerjee: The Francis Crick Institute
Simon Hauri: Institute of Molecular Systems Biology, ETH Zürich
Nicola O’Reilly: Peptide Chemistry Laboratory, The Francis Crick Institute
Matthias Gstaiger: Institute of Molecular Systems Biology, ETH Zürich
Rebecca Page: University of Arizona
Wolfgang Peti: University of Arizona
Nicolas Tapon: The Francis Crick Institute

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract Serine/threonine phosphatases such as PP1 lack substrate specificity and associate with a large array of targeting subunits to achieve the requisite selectivity. The tumour suppressor ASPP (apoptosis-stimulating protein of p53) proteins associate with PP1 catalytic subunits and are implicated in multiple functions from transcriptional regulation to cell junction remodelling. Here we show that Drosophila ASPP is part of a multiprotein PP1 complex and that PP1 association is necessary for several in vivo functions of Drosophila ASPP. We solve the crystal structure of the human ASPP2/PP1 complex and show that ASPP2 recruits PP1 using both its canonical RVxF motif, which binds the PP1 catalytic domain, and its SH3 domain, which engages the PP1 C-terminal tail. The ASPP2 SH3 domain can discriminate between PP1 isoforms using an acidic specificity pocket in the n-Src domain, providing an exquisite mechanism where multiple motifs are used combinatorially to tune binding affinity to PP1.

Date: 2019
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DOI: 10.1038/s41467-019-08686-0

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