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- Title
SDS22 coordinates the assembly of holoenzymes from nascent protein phosphatase-1.
- Authors
Cao, Xinyu; Lake, Madryn; Van der Hoeven, Gerd; Claes, Zander; del Pino García, Javier; Lemaire, Sarah; Greiner, Elora C.; Karamanou, Spyridoula; Van Eynde, Aleyde; Kettenbach, Arminja N.; Natera de Benito, Daniel; Carrera García, Laura; Hernando Davalillo, Cristina; Ortez, Carlos; Nascimento, Andrés; Urreizti, Roser; Bollen, Mathieu
- 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. SDS22 is a poorly characterized regulator of PP1. Here, the authors show that SDS22 prevents the aggregation of nascent PP1 and coordinates its stepwise incorporation into functional holoenzymes.
- Subjects
PHOSPHOPROTEIN phosphatases; BINDING sites; ADENOSINE triphosphatase; PROTEINS; PROTEIN kinase CK2; PHOSPHORYLATION
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49746-4