5nvm

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Crystal structure of the human 4EHP-GIGYF2 complex lacking the auxiliary sequencesCrystal structure of the human 4EHP-GIGYF2 complex lacking the auxiliary sequences

Structural highlights

5nvm is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:EIF4E2, EIF4EL3 (HUMAN), GIGYF2, KIAA0642, PERQ2, TNRC15 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[GGYF2_HUMAN] Young adult-onset Parkinsonism. Disease susceptibility may be associated with variations affecting the gene represented in this entry. Its association with Parkinson disease is however unclear. According to a number of studies, variations affecting this gene are not a frequent cause of Parkinson disease, suggesting that GIGYF2 does not play a major role in Parkinson disease etiology (PubMed:19279319, PubMed:19429085, PubMed:19638301, PubMed:19482505, PubMed:20004041, PubMed:19321232, PubMed:20060621).[1] [2] [3] [4] [5] [6] [7]

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][8] [9] [10] [11] [GGYF2_HUMAN] Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation (PubMed:22751931). In 4EHP-GYF2 the complex, acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking translation repression with mRNA decay (By similarity). May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling, including IGF1 and insulin receptors (PubMed:12771153).[UniProtKB:Q6Y7W8][12] [13]

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[14]

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

References

  1. ↑ Nichols WC, Kissell DK, Pankratz N, Pauciulo MW, Elsaesser VE, Clark KA, Halter CA, Rudolph A, Wojcieszek J, Pfeiffer RF, Foroud T. Variation in GIGYF2 is not associated with Parkinson disease. Neurology. 2009 Jun 2;72(22):1886-92. doi: 10.1212/01.wnl.0000346517.98982.1b., Epub 2009 Mar 11. PMID:19279319 doi:http://dx.doi.org/10.1212/01.wnl.0000346517.98982.1b
  2. ↑ Meeus B, Nuytemans K, Crosiers D, Engelborghs S, Pals P, Pickut B, Peeters K, Mattheijssens M, Corsmit E, Cras P, De Deyn PP, Theuns J, Van Broeckhoven C. GIGYF2 has no major role in Parkinson genetic etiology in a Belgian population. Neurobiol Aging. 2011 Feb;32(2):308-12. doi:, 10.1016/j.neurobiolaging.2009.02.016. Epub 2009 Mar 24. PMID:19321232 doi:http://dx.doi.org/10.1016/j.neurobiolaging.2009.02.016
  3. ↑ Guo Y, Jankovic J, Zhu S, Le W, Song Z, Xie W, Liao D, Yang H, Deng H. GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients. Neurosci Lett. 2009 May 1;454(3):209-11. doi: 10.1016/j.neulet.2009.03.039. Epub , 2009 Mar 16. PMID:19429085 doi:http://dx.doi.org/10.1016/j.neulet.2009.03.039
  4. ↑ Di Fonzo A, Fabrizio E, Thomas A, Fincati E, Marconi R, Tinazzi M, Breedveld GJ, Simons EJ, Chien HF, Ferreira JJ, Horstink MW, Abbruzzese G, Borroni B, Cossu G, Dalla Libera A, Fabbrini G, Guidi M, De Mari M, Lopiano L, Martignoni E, Marini P, Onofrj M, Padovani A, Stocchi F, Toni V, Sampaio C, Barbosa ER, Meco G, Oostra BA, Bonifati V. GIGYF2 mutations are not a frequent cause of familial Parkinson's disease. Parkinsonism Relat Disord. 2009 Nov;15(9):703-5. doi:, 10.1016/j.parkreldis.2009.05.001. Epub 2009 May 31. PMID:19482505 doi:http://dx.doi.org/10.1016/j.parkreldis.2009.05.001
  5. ↑ Zhang Y, Zheng L, Zhang T, Wang Y, Xiao Q, Fei QZ, Cui PJ, Cao L, Chen SD. GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson's disease patients. Neurosci Lett. 2009 Oct 9;463(3):172-5. doi: 10.1016/j.neulet.2009.07.067. Epub, 2009 Jul 26. PMID:19638301 doi:http://dx.doi.org/10.1016/j.neulet.2009.07.067
  6. ↑ Lesage S, Condroyer C, Lohman E, Troiano A, Tison F, Viallet F, Damier P, Tranchant C, Vidhaillet M, Ouvrard-Hernandez AM, Durr A, Brice A. Follow-up study of the GIGYF2 gene in French families with Parkinson's disease. Neurobiol Aging. 2010 Jun;31(6):1069-71; discussion 1072-4. doi:, 10.1016/j.neurobiolaging.2009.06.008. Epub 2009 Dec 8. PMID:20004041 doi:http://dx.doi.org/10.1016/j.neurobiolaging.2009.06.008
  7. ↑ Guella I, Pistocchi A, Asselta R, Rimoldi V, Ghilardi A, Sironi F, Trotta L, Primignani P, Zini M, Zecchinelli A, Coviello D, Pezzoli G, Del Giacco L, Duga S, Goldwurm S. Mutational screening and zebrafish functional analysis of GIGYF2 as a Parkinson-disease gene. Neurobiol Aging. 2011 Nov;32(11):1994-2005. doi:, 10.1016/j.neurobiolaging.2009.12.016. Epub 2010 Jan 8. PMID:20060621 doi:http://dx.doi.org/10.1016/j.neurobiolaging.2009.12.016
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ Giovannone B, Lee E, Laviola L, Giorgino F, Cleveland KA, Smith RJ. Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling. J Biol Chem. 2003 Aug 22;278(34):31564-73. Epub 2003 May 27. PMID:12771153 doi:http://dx.doi.org/10.1074/jbc.M211572200
  13. ↑ 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
  14. ↑ 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

5nvm, resolution 2.00Å

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