2gk7

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Structural and Functional insights into the human Upf1 helicase core

Structural highlights

2gk7 is a 1 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:X-ray diffraction, Resolution 2.8Å
Ligands:PO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RENT1_HUMAN RNA-dependent helicase and ATPase required for nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Is recruited to mRNAs upon translation termination and undergoes a cycle of phosphorylation and dephosphorylation; its phosphorylation appears to be a key step in NMD. Recruited by release factors to stalled ribosomes together with the SMG1C protein kinase complex to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) (located 50-55 or more nucleotides downstream from the termination codon) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Phosphorylated UPF1 is recognized by EST1B/SMG5, SMG6 and SMG7 which are thought to provide a link to the mRNA degradation machinery involving exonucleolytic and endonucleolytic pathways, and to serve as adapters to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation and allowing the recycling of NMD factors. UPF1 can also activate NMD without UPF2 or UPF3, and in the absence of the NMD-enhancing downstream EJC indicative for alternative NMD pathways. Plays a role in replication-dependent histone mRNA degradation at the end of phase S; the function is independent of UPF2. For the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed. The ATPase activity of UPF1 is required for disassembly of mRNPs undergoing NMD. Essential for embryonic viability.[1] [2] [3] [4] [5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance pathway that recognizes and degrades aberrant mRNAs containing premature stop codons. A critical protein in NMD is Upf1p, which belongs to the helicase super family 1 (SF1), and is thought to utilize the energy of ATP hydrolysis to promote transitions in the structure of RNA or RNA-protein complexes. The crystal structure of the catalytic core of human Upf1p determined in three states (phosphate-, AMPPNP- and ADP-bound forms) reveals an overall structure containing two RecA-like domains with two additional domains protruding from the N-terminal RecA-like domain. Structural comparison combined with mutational analysis identifies a likely single-stranded RNA (ssRNA)-binding channel, and a cycle of conformational change coupled to ATP binding and hydrolysis. These conformational changes alter the likely ssRNA-binding channel in a manner that can explain how ATP binding destabilizes ssRNA binding to Upf1p.

Structural and functional insights into the human Upf1 helicase core.,Cheng Z, Muhlrad D, Lim MK, Parker R, Song H EMBO J. 2007 Jan 10;26(1):253-64. Epub 2006 Dec 7. PMID:17159905[6]

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

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References

  1. ↑ Lykke-Andersen J, Shu MD, Steitz JA. Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell. 2000 Dec 22;103(7):1121-31. PMID:11163187
  2. ↑ Kaygun H, Marzluff WF. Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1. Nat Struct Mol Biol. 2005 Sep;12(9):794-800. Epub 2005 Aug 7. PMID:16086026 doi:http://dx.doi.org/10.1038/nsmb972
  3. ↑ Mullen TE, Marzluff WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5' to 3' and 3' to 5'. Genes Dev. 2008 Jan 1;22(1):50-65. doi: 10.1101/gad.1622708. PMID:18172165 doi:10.1101/gad.1622708
  4. ↑ Franks TM, Singh G, Lykke-Andersen J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell. 2010 Dec 10;143(6):938-50. doi: 10.1016/j.cell.2010.11.043. PMID:21145460 doi:http://dx.doi.org/10.1016/j.cell.2010.11.043
  5. ↑ Chakrabarti S, Jayachandran U, Bonneau F, Fiorini F, Basquin C, Domcke S, Le Hir H, Conti E. Molecular Mechanisms for the RNA-Dependent ATPase Activity of Upf1 and Its Regulation by Upf2. Mol Cell. 2011 Mar 18;41(6):693-703. PMID:21419344 doi:10.1016/j.molcel.2011.02.010
  6. ↑ Cheng Z, Muhlrad D, Lim MK, Parker R, Song H. Structural and functional insights into the human Upf1 helicase core. EMBO J. 2007 Jan 10;26(1):253-64. Epub 2006 Dec 7. PMID:17159905

Contents


PDB ID 2gk7

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