5W0W

Crystal structure of Protein Phosphatase 2A bound to TIPRL

Summary for 5W0W

• Entry DOI: 10.2210/pdb5w0w/pdb
• Descriptor: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform, TIP41-like protein, Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform, ... (4 entities in total)
• Functional Keywords: complex phosphotase phosphotase regulator, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 522324.44

Authors

Wu, C.,Zheng, A.,Li, J.,Satyshur, K.,Xing, Y. (deposition date: 2017-06-01, release date: 2018-01-17, Last modification date: 2024-11-20)

Primary citation

Wu, C.G.,Zheng, A.,Jiang, L.,Rowse, M.,Stanevich, V.,Chen, H.,Li, Y.,Satyshur, K.A.,Johnson, B.,Gu, T.J.,Liu, Z.,Xing, Y.
Methylation-regulated decommissioning of multimeric PP2A complexes.
Nat Commun, 8:2272-2272, 2017

PubMed Abstract: Dynamic assembly/disassembly of signaling complexes are crucial for cellular functions. Specialized latency and activation chaperones control the biogenesis of protein phosphatase 2A (PP2A) holoenzymes that contain a common scaffold and catalytic subunits and a variable regulatory subunit. Here we show that the butterfly-shaped TIPRL (TOR signaling pathway regulator) makes highly integrative multibranching contacts with the PP2A catalytic subunit, selective for the unmethylated tail and perturbing/inactivating the phosphatase active site. TIPRL also makes unusual wobble contacts with the scaffold subunit, allowing TIPRL, but not the overlapping regulatory subunits, to tolerate disease-associated PP2A mutations, resulting in reduced holoenzyme assembly and enhanced inactivation of mutant PP2A. Strikingly, TIPRL and the latency chaperone, α4, coordinate to disassemble active holoenzymes into latent PP2A, strictly controlled by methylation. Our study reveals a mechanism for methylation-responsive inactivation and holoenzyme disassembly, illustrating the complexity of regulation/signaling, dynamic complex disassembly, and disease mutations in cancer and intellectual disability.

PubMed: 29273778
DOI: 10.1038/s41467-017-02405-3

Experimental method

X-RAY DIFFRACTION (3.8 Å)