Movie
Controller
Structure viewers
About Yorodumi Papers
+Search query
-Structure paper
| Title | B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 121, Issue 1, Page e2310727120, Year 2024 |
| Publish date | Jan 2, 2024 |
 Authors | Cheng-Guo Wu / Vijaya K Balakrishnan / Ronald A Merrill / Pankaj S Parihar / Kirill Konovolov / Yu-Chia Chen / Zhen Xu / Hui Wei / Ramya Sundaresan / Qiang Cui / Brian E Wadzinski / Mark R Swingle / Alla Musiyenko / Wendy K Chung / Richard E Honkanen / Aussie Suzuki / Xuhui Huang / Stefan Strack / Yongna Xing /  |
| PubMed Abstract | Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by ) is a regulatory ...Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by ) is a regulatory subunit of protein phosphatase 2A (PP2A) with long IDRs that harbor a substrate-mimicking SLiM and multiple phosphorylation sites. De novo missense mutations in cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Our single-particle cryo-EM structures of the PP2A-B56δ holoenzyme reveal that the long, disordered arms at the B56δ termini fold against each other and the holoenzyme core. This architecture suppresses both the phosphatase active site and the substrate-binding protein groove, thereby stabilizing the enzyme in a closed latent form with dual autoinhibition. The resulting interface spans over 190 Å and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is coupled to an allosteric network responsive to phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations increase the holoenzyme activity and perturb the phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the normal variant. |
 External links | Proc Natl Acad Sci U S A / PubMed:38150499 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.7 - 3.3 Å |
| Structure data | EMDB-41837, PDB-8u1x: EMDB-42018, PDB-8u89: |
| Chemicals |  ChemComp-MN: |
| Source |
|
 Keywords |  CELL CYCLE / complex / phosphatase |
