Inhibitor-2 directs formation of PP1 holoenzymes through a docking motif-dependent transfer of catalytic subunits to adapters
Varshney, N.; Schlientz, A. J.; Meaders, J. L.; Oegema, K.; Desai, A.
Show abstract
The catalytic subunits of protein phosphatase 1 (PP1) achieve spatiotemporal substrate specificity by assembling with diverse regulatory adapters to form holoenzymes. Three conserved proteins--Sds22, Inhibitor-2 and Inhibitor-3--facilitate loading of PP1 catalytic subunits (PP1cs) onto adapters. We show here that Inhibitor-2 is central to a dynamic cycle that directs formation of adapter-bound PP1 holoenzymes. Inhibitor-2 engages PP1cs via two adapter-like docking motifs (RVxF and SILK) and an active site-binding inhibitory region. While Inhibitor-2 depletion produced moderate phenotypes, mutation of its RVxF docking motif caused severe defects resembling global PP1c inhibition. The RVxF mutant did not prevent PP1c binding or reduce PP1c stability but inhibited formation of adapter-bound holoenzymes. The severe effects of the RVxF mutation were suppressed by linked mutation of the inhibitory active site-binding motif. These results suggest that Inhibitor-2 is integral to a dynamic cycle that delivers PP1cs to adapters, with its RVxF motif being critical for coupling relief of active site inhibition to adapter handoff.
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