Joshua Mayfield (University of California - San Diego), Alexandra Newton (University of California - San Diego), Jack Dixon (University of California - San Diego)
Presenting Author University of California - San Diego
Divalent cations are essential to cellular processes through interaction with biological macromolecules, involvement in enzyme-mediated catalysis, and as secondary messengers in signaling cascades. Recently, we have discovered divalent cation driven liquid-liquid phase separation (LLPS) underlies endoplasmic reticulum Ca2+ stores through disordered acidic calcium binding protein calsequestrin-1 (CASQ1). CASQ1 interacts with divalent cations to enter a LLPS state via complex coacervation. CASQ1 LLPS propensity is positively regulated by FAM20C-dependent phosphorylation that induces an order-to-disorder transition accompanied by dramatic structural expansion. These events increase intracellular Ca2+ stores and regulate cellular stress response. Proteome wide analysis of disordered acidic proteins suggests divalent cation driven LLPS may be an emerging mechanism extending beyond the ER. Particularly, these proteins are highly enriched in the nucleus and cytosol where they accumulate in a number of biological condensates alongside other polyanions like RNA to regulate gene expression. We hypothesize divalent cation driven LLPS is a widespread mechanism driving both protein-protein and protein-nucleic acid interactions.
