Structure-Guided Exploration of SDS22 Interactions with Protein Phosphatase PP1 and the Splicing Factor BCLAF1.

Summary SDS22 is an ancient regulator of protein phosphatase-1 (PP1). Our crystal structure of SDS22 shows that its twelve leucine-rich repeats adopt a banana-shaped fold that is shielded from solvent by capping domains at its extremities. Subsequent modeling and biochemical studies revealed that the concave side of SDS22 likely interacts with PP1 helices α5 and α6, which are distal from the binding sites of many previously described PP1 interactors. Accordingly, we found that SDS22 acts as a "third" subunit of multiple PP1 holoenzymes. The crystal structure of SDS22 also revealed a large basic surface patch that enables binding of a phosphorylated form of splicing factor BCLAF1. Taken together, our data provide insights into the formation of PP1:SDS22 and the recruitment of additional interaction proteins, such as BCLAF1. Graphical Abstract Highlights • The LRRs of SDS22 interact with PP1 helices α5 and α6 • A basic surface patch of SDS22 binds phosphorylated BCLAF1 • Many PP1 holoenzymes contain SDS22 as a third subunit • SDS22 prevents the autodephosphorylation of PP1 The function of protein phosphatase 1 (PP1) is determined by associated regulatory proteins. Heroes et al. describe the structure of the PP1 regulator SDS22, which largely consists of leucine-rich repeats. They also present a biochemically validated model of the PP1:SDS22 complex and use it as a guide for functional studies. [ABSTRACT FROM AUTHOR]