6VTI

Solution NMR structure of the N-terminal domain of the Serine/threonine-protein phosphatase 1 regulatory subunit 10, PPP1R10

Summary for 6VTI

• Entry DOI: 10.2210/pdb6vti/pdb
• NMR Information: BMRB: 30722
• Descriptor: Serine/threonine-protein phosphatase 1 regulatory subunit 10 (1 entity in total)
• Functional Keywords: pp1-pnuts phosphatase complex, regulatory subunit, c-myc oncoprotein, nuclear protein
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 16648.48

Authors

Lemak, A.,Wei, Y.,Duan, S.,Houliston, S.,Penn, L.Z.,Arrowsmith, C.H. (deposition date: 2020-02-12, release date: 2020-02-26, Last modification date: 2024-05-15)

Primary citation

Wei, Y.,Redel, C.,Ahlner, A.,Lemak, A.,Johansson-Akhe, I.,Houliston, S.,Kenney, T.M.G.,Tamachi, A.,Morad, V.,Duan, S.,Andrews, D.W.,Wallner, B.,Sunnerhagen, M.,Arrowsmith, C.H.,Penn, L.Z.
The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase.
Nucleic Acids Res., 50:3505-3522, 2022

PubMed Abstract: Despite MYC dysregulation in most human cancers, strategies to target this potent oncogenic driver remain an urgent unmet need. Recent evidence shows the PP1 phosphatase and its regulatory subunit PNUTS control MYC phosphorylation, chromatin occupancy, and stability, however the molecular basis remains unclear. Here we demonstrate that MYC interacts directly with PNUTS through the MYC homology Box 0 (MB0), a highly conserved region recently shown to be important for MYC oncogenic activity. By NMR we identified a distinct peptide motif within MB0 that interacts with PNUTS residues 1-148, a functional unit, here termed PNUTS amino-terminal domain (PAD). Using NMR spectroscopy we determined the solution structure of PAD, and characterised its MYC-binding patch. Point mutations of residues at the MYC-PNUTS interface significantly weaken their interaction both in vitro and in vivo, leading to elevated MYC phosphorylation. These data demonstrate that the MB0 region of MYC directly interacts with the PAD of PNUTS, which provides new insight into the control mechanisms of MYC as a regulator of gene transcription and a pervasive cancer driver.

PubMed: 35244724
DOI: 10.1093/nar/gkac138

Experimental method

SOLUTION NMR