Abstract
An increasing number of mutations associated with devastating human diseases are being diagnosed by whole-genome/exon sequencing. Up to twenty de novo mutations have been discovered in B56δ (encoded by PPP2R5D), a regulatory subunit of protein phosphatase 2A (PP2A), that cause intellectual disabilities (ID) and a broad range of neurological symptoms. Single-particle cryo-EM structures show that the PP2A-B56δ holoenzyme possesses closed latent and open active forms. In the closed form, the long, disordered arms of B56δ termini fold against each other and the holoenzyme core, and establish dual autoinhibition of the phosphatase active site and the substrate-binding protein groove. The resulting interface spans over 190 Å and harbors unfavorable contacts, as well as activation phosphorylation sites and nearly all residues with ID-associated mutations. Our studies suggest that this super-dynamic interface is close to an allosteric network that is responsive to activation phosphorylation and is altered globally by ID mutations. We further showed that ID mutations perturbed the activation phosphorylation rates, mitotic progression, and mitotic error rates.
Competing Interest Statement
The authors have declared no competing interest.
