7lqt
From Proteopedia
Solution NMR structure of the PNUTS amino-terminal Domain fused to Myc Homology Box 0
Structural highlights
FunctionMYC_RAT Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3'. Activates the transcription of growth-related genes (PubMed:17304222). Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis (By similarity). Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release (By similarity). Positively regulates transcription of HNRNPA1, HNRNPA2 and PTBP1 which in turn regulate splicing of pyruvate kinase PKM by binding repressively to sequences flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (By similarity).[UniProtKB:P01106][UniProtKB:P01108][1] PP1RA_RAT Scaffold protein which mediates the formation of the PTW/PP1 phosphatase complex by providing a binding platform to each component of the complex. The PTW/PP1 phosphatase complex plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Mediates interaction of WDR82 and PPP1CA. Inhibitor of PPP1CA and PPP1CC phosphatase activities. Has inhibitory activity on PPP1CA only when phosphorylated. Binds to mRNA, single-stranded DNA (ssDNA), poly(A) and poly(G) homopolymers.[2] [3] Publication Abstract from PubMedDespite 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. The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase.,Wei Y, Redel C, Ahlner A, Lemak A, Johansson-Akhe I, Houliston S, Kenney TMG, Tamachi A, Morad V, Duan S, Andrews DW, Wallner B, Sunnerhagen M, Arrowsmith CH, Penn LZ Nucleic Acids Res. 2022 Mar 4. pii: 6542486. doi: 10.1093/nar/gkac138. PMID:35244724[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||
Categories: Large Structures | Rattus norvegicus | Arrowsmith CH | Duan S | Houliston S | Lemak A | Penn LZ | Wei Y
