6z3r

Structure of SMG1-8-9 kinase complex bound to UPF1-LSQStructure of SMG1-8-9 kinase complex bound to UPF1-LSQ

Structural highlights

6z3r is a 4 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 2.97Å
Ligands:	, , ,
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

PI3K-related kinases (PIKKs) are large Serine/Threonine (Ser/Thr)-protein kinases central to the regulation of many fundamental cellular processes. PIKK family member SMG1 orchestrates progression of an RNA quality control pathway, termed nonsense-mediated mRNA decay (NMD), by phosphorylating the NMD factor UPF1. Phosphorylation of UPF1 occurs in its unstructured N- and C-terminal regions at Serine/Threonine-Glutamine (SQ) motifs. How SMG1 and other PIKKs specifically recognize SQ motifs has remained unclear. Here, we present a cryo-electron microscopy (cryo-EM) reconstruction of a human SMG1-8-9 kinase complex bound to a UPF1 phosphorylation site at an overall resolution of 2.9 A. This structure provides the first snapshot of a human PIKK with a substrate-bound active site. Together with biochemical assays, it rationalizes how SMG1 and perhaps other PIKKs specifically phosphorylate Ser/Thr-containing motifs with a glutamine residue at position +1 and a hydrophobic residue at position -1, thus elucidating the molecular basis for phosphorylation site recognition.

Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity.,Langer LM, Gat Y, Bonneau F, Conti E Elife. 2020 May 29;9. pii: 57127. doi: 10.7554/eLife.57127. PMID:32469312^[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
↑ Langer LM, Gat Y, Bonneau F, Conti E. Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity. Elife. 2020 May 29;9. pii: 57127. doi: 10.7554/eLife.57127. PMID:32469312 doi:http://dx.doi.org/10.7554/eLife.57127

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] Langer LM, Gat Y, Bonneau F, Conti E. Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity. Elife. 2020 May 29;9. pii: 57127. doi: 10.7554/eLife.57127. PMID:32469312 doi:http://dx.doi.org/10.7554/eLife.57127

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