6syt

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Structure of the SMG1-SMG8-SMG9 complex

6syt, resolution 3.45Å

Structural highlights

6syt is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.45Å
Ligands:
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SMG1_HUMAN Serine/threonine protein kinase involved in both mRNA surveillance and genotoxic stress response pathways. Recognizes the substrate consensus sequence [ST]-Q. Plays a central role in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by phosphorylating UPF1/RENT1. Recruited by release factors to stalled ribosomes together with SMG8 and SMG9 (forming the SMG1C protein kinase complex), and UPF1 to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Also acts as a genotoxic stress-activated protein kinase that displays some functional overlap with ATM. Can phosphorylate p53/TP53 and is required for optimal p53/TP53 activation after cellular exposure to genotoxic stress. Its depletion leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). May activate PRKCI but not PRKCZ.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

We report the 3.45-A resolution cryo-EM structure of human SMG1-SMG8-SMG9, a phosphatidylinositol-3-kinase (PI(3)K)-related protein kinase (PIKK) complex central to messenger RNA surveillance. Structural and MS analyses reveal the presence of inositol hexaphosphate (InsP6) in the SMG1 kinase. We show that the InsP6-binding site is conserved in mammalian target of rapamycin (mTOR) and potentially other PIKK members, and that it is required for optimal in vitro phosphorylation of both SMG1 and mTOR substrates.

InsP6 binding to PIKK kinases revealed by the cryo-EM structure of an SMG1-SMG8-SMG9 complex.,Gat Y, Schuller JM, Lingaraju M, Weyher E, Bonneau F, Strauss M, Murray PJ, Conti E Nat Struct Mol Biol. 2019 Dec;26(12):1089-1093. doi: 10.1038/s41594-019-0342-7., Epub 2019 Dec 2. PMID:31792449^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Denning G, Jamieson L, Maquat LE, Thompson EA, Fields AP. Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein. J Biol Chem. 2001 Jun 22;276(25):22709-14. PMID:11331269 doi:10.1074/jbc.C100144200
↑ Yamashita A, Ohnishi T, Kashima I, Taya Y, Ohno S. Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 2001 Sep 1;15(17):2215-28. PMID:11544179 doi:10.1101/gad.913001
↑ Brumbaugh KM, Otterness DM, Geisen C, Oliveira V, Brognard J, Li X, Lejeune F, Tibbetts RS, Maquat LE, Abraham RT. The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. Mol Cell. 2004 Jun 4;14(5):585-98. PMID:15175154 doi:10.1016/j.molcel.2004.05.005
↑ Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, Ohno M, Dreyfuss G, Ohno S. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev. 2006 Feb 1;20(3):355-67. PMID:16452507 doi:10.1101/gad.1389006
↑ Gat Y, Schuller JM, Lingaraju M, Weyher E, Bonneau F, Strauss M, Murray PJ, Conti E. InsP6 binding to PIKK kinases revealed by the cryo-EM structure of an SMG1-SMG8-SMG9 complex. Nat Struct Mol Biol. 2019 Dec;26(12):1089-1093. doi: 10.1038/s41594-019-0342-7., Epub 2019 Dec 2. PMID:31792449 doi:http://dx.doi.org/10.1038/s41594-019-0342-7