5nvk

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Crystal structure of the human 4EHP-GIGYF1 complex

Structural highlights

5nvk is a 8 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 2.9Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IF4E2_HUMAN Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation (PubMed:9582349, PubMed:17368478, PubMed:25624349). Acts as a repressor of translation initiation (PubMed:22751931). In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap (By similarity).[UniProtKB:Q8BMB3][1] [2] [3] [4]

Publication Abstract from PubMed

The eIF4E homologous protein (4EHP) is thought to repress translation by competing with eIF4E for binding to the 5' cap structure of specific mRNAs to which it is recruited through interactions with various proteins, including the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins 1 and 2 (GIGYF1/2). Despite its similarity to eIF4E, 4EHP does not interact with eIF4G and therefore fails to initiate translation. In contrast to eIF4G, GIGYF1/2 bind selectively to 4EHP but not eIF4E. Here, we present crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP, which reveal the molecular basis for the selectivity of the GIGYF1/2 proteins for 4EHP. Complementation assays in a GIGYF1/2-null cell line using structure-based mutants indicate that 4EHP requires interactions with GIGYF1/2 to down-regulate target mRNA expression. Our studies provide structural insights into the assembly of 4EHP-GIGYF1/2 repressor complexes and reveal that rather than merely facilitating 4EHP recruitment to transcripts, GIGYF1/2 proteins are required for repressive activity.

GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression.,Peter D, Weber R, Sandmeir F, Wohlbold L, Helms S, Bawankar P, Valkov E, Igreja C, Izaurralde E Genes Dev. 2017 Jun 1;31(11):1147-1161. doi: 10.1101/gad.299420.117. Epub 2017, Jul 11. PMID:28698298[5]

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

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Citations
6 reviews cite this structure
Getting to the Cores of Autism.
Iakoucheva et al. (2019)
5 more
36 other articles
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See Also

References

  1. ↑ Rosettani P, Knapp S, Vismara MG, Rusconi L, Cameron AD. Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms. J Mol Biol. 2007 May 4;368(3):691-705. Epub 2007 Feb 20. PMID:17368478 doi:10.1016/j.jmb.2007.02.019
  2. ↑ Morita M, Ler LW, Fabian MR, Siddiqui N, Mullin M, Henderson VC, Alain T, Fonseca BD, Karashchuk G, Bennett CF, Kabuta T, Higashi S, Larsson O, Topisirovic I, Smith RJ, Gingras AC, Sonenberg N. A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Mol Cell Biol. 2012 Sep;32(17):3585-93. doi: 10.1128/MCB.00455-12. Epub 2012 Jul , 2. PMID:22751931 doi:http://dx.doi.org/10.1128/MCB.00455-12
  3. ↑ von Stechow L, Typas D, Carreras Puigvert J, Oort L, Siddappa R, Pines A, Vrieling H, van de Water B, Mullenders LH, Danen EH. The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. Mol Cell Biol. 2015 Apr;35(7):1254-68. doi: 10.1128/MCB.01152-14. Epub 2015 Jan, 26. PMID:25624349 doi:http://dx.doi.org/10.1128/MCB.01152-14
  4. ↑ Rom E, Kim HC, Gingras AC, Marcotrigiano J, Favre D, Olsen H, Burley SK, Sonenberg N. Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein. J Biol Chem. 1998 May 22;273(21):13104-9. PMID:9582349
  5. ↑ Peter D, Weber R, Sandmeir F, Wohlbold L, Helms S, Bawankar P, Valkov E, Igreja C, Izaurralde E. GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression. Genes Dev. 2017 Jun 1;31(11):1147-1161. doi: 10.1101/gad.299420.117. Epub 2017, Jul 11. PMID:28698298 doi:http://dx.doi.org/10.1101/gad.299420.117

Contents


PDB ID 5nvk

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