SDS22 coordinates the assembly of holoenzymes from nascent protein phosphatase-1

Xinyu Cao, Madryn Lake, Gerd Hoeven, Zander Claes, Javier del Pino García, Sarah Lemaire, Elora C. Greiner, Spyridoula Karamanou, Aleyde Eynde, Arminja N. Kettenbach, Daniel Natera de Benito, Laura Carrera García, Cristina Hernando Davalillo, Carlos Ortez, Andrés Nascimento, Roser Urreizti and Mathieu Bollen ()
Additional contact information
Xinyu Cao: University of Leuven
Madryn Lake: University of Leuven
Gerd Hoeven: University of Leuven
Zander Claes: University of Leuven
Javier del Pino García: University of Leuven
Sarah Lemaire: University of Leuven
Elora C. Greiner: Geisel School of Medicine at Dartmouth
Spyridoula Karamanou: University of Leuven
Aleyde Eynde: University of Leuven
Arminja N. Kettenbach: Geisel School of Medicine at Dartmouth
Daniel Natera de Benito: Hospital Sant Joan de Deu
Laura Carrera García: Hospital Sant Joan de Deu
Cristina Hernando Davalillo: Hospital Sant Joan de Deu
Carlos Ortez: Hospital Sant Joan de Deu
Andrés Nascimento: Hospital Sant Joan de Deu
Roser Urreizti: Hospital Sant Joan de Deu
Mathieu Bollen: University of Leuven

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract SDS22 forms an inactive complex with nascent protein phosphatase PP1 and Inhibitor-3. SDS22:PP1:Inhibitor-3 is a substrate for the ATPase p97/VCP, which liberates PP1 for binding to canonical regulatory subunits. The exact role of SDS22 in PP1-holoenzyme assembly remains elusive. Here, we show that SDS22 stabilizes nascent PP1. In the absence of SDS22, PP1 is gradually lost, resulting in substrate hyperphosphorylation and a proliferation arrest. Similarly, we identify a female individual with a severe neurodevelopmental disorder bearing an unstable SDS22 mutant, associated with decreased PP1 levels. We furthermore find that SDS22 directly binds to Inhibitor-3 and that this is essential for the stable assembly of SDS22:PP1: Inhibitor-3, the recruitment of p97/VCP, and the extraction of SDS22 during holoenzyme assembly. SDS22 with a disabled Inhibitor-3 binding site co-transfers with PP1 to canonical regulatory subunits, thereby forming non-functional holoenzymes. Our data show that SDS22, through simultaneous interaction with PP1 and Inhibitor-3, integrates the major steps of PP1 holoenzyme assembly.

Date: 2024
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DOI: 10.1038/s41467-024-49746-4

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