High resolution interaction surface mapping by PRISMA reveals novel ARID1A interactions

Background The cBAF SWI/SNF chromatin remodelling complex controls cell proliferation and fate determination by regulating chromatin accessibility and programs of gene expression, DNA damage response, replication, splicing, translation, and cell plasticity. This functional diversity stems from varied protein interactions. ARID1A is the most frequently mutated SWI/SNF subunit in cancer and scaffold of cBAF through the globular C-terminal domain. The rest of ARID1A mostly contains intrinsically disordered regions, key interaction surfaces that are notoriously difficult to study due to highly dynamic conformations. The molecular basis of ARID1A interactions remains obscure, and few have been explored functionally or mapped at an interface level. We perform a PRotein Interaction Screen on peptide MAtrix (PRISMA) to identify novel ARID1A interactions and map short linear motifs that mediate interactions at high sequence resolution. Results Our PRISMA assay recapitulates binding sites of cBAF subunits to ARID1A and detects previously described SLiM-mediated interactions. We reveal binding sites for direct interaction with transcriptional repressor SIN3A, interaction and confirm its role in SIN3A chromatin recruitment. We identify TOX4, CDK2 and CCNA2 as novel ARID1A interactors. Mutation of a cell cycle-regulated CDK2 phosphorylation site in ARID1A leads to altered gene expression of microtubule factors and defective cell division. Conclusions Our study provides novel mechanistic insight into ARID1A functions and highlights a role for CDK2-dependent phosphorylation of ARID1A in the regulation of cell division, with important ramifications for cancer. Our data represents a valuable resource to further study ARID1A and SWI/SNF biology, and more broadly, to investigate sequence and structural features governing protein interactions.