5bxv

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Revision as of 13:22, 10 May 2017

eIF4E complex

Structural highlights

5bxv is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[IF4E_MOUSE] Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (By similarity). Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap.^[1] [4EBP1_HUMAN] Regulates eIF4E activity by preventing its assembly into the eIF4F complex. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.^[2]

Publication Abstract from PubMed

The eIF4E-binding protein (4E-BP) is a phosphorylation-dependent regulator of protein synthesis. The nonphosphorylated or minimally phosphorylated form binds translation initiation factor 4E (eIF4E), preventing binding of eIF4G and the recruitment of the small ribosomal subunit. Signaling events stimulate serial phosphorylation of 4E-BP, primarily by mammalian target of rapamycin complex 1 (mTORC1) at residues T37/T46, followed by T70 and S65. Hyperphosphorylated 4E-BP dissociates from eIF4E, allowing eIF4E to interact with eIF4G and translation initiation to resume. Because overexpression of eIF4E is linked to cellular transformation, 4E-BP is a tumor suppressor, and up-regulation of its activity is a goal of interest for cancer therapy. A recently discovered small molecule, eIF4E/eIF4G interaction inhibitor 1 (4EGI-1), disrupts the eIF4E/eIF4G interaction and promotes binding of 4E-BP1 to eIF4E. Structures of 14- to 16-residue 4E-BP fragments bound to eIF4E contain the eIF4E consensus binding motif, 54YXXXXLPhi60 (motif 1) but lack known phosphorylation sites. We report here a 2.1-A crystal structure of mouse eIF4E in complex with m7GTP and with a fragment of human 4E-BP1, extended C-terminally from the consensus-binding motif (4E-BP150-84). The extension, which includes a proline-turn-helix segment (motif 2) followed by a loop of irregular structure, reveals the location of two phosphorylation sites (S65 and T70). Our major finding is that the C-terminal extension (motif 3) is critical to 4E-BP1-mediated cell cycle arrest and that it partially overlaps with the binding site of 4EGI-1. The binding of 4E-BP1 and 4EGI-1 to eIF4E is therefore not mutually exclusive, and both ligands contribute to shift the equilibrium toward the inhibition of translation initiation.

Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1.,Sekiyama N, Arthanari H, Papadopoulos E, Rodriguez-Mias RA, Wagner G, Leger-Abraham M Proc Natl Acad Sci U S A. 2015 Jul 13. pii: 201512118. PMID:26170285^[3]

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

References

↑ Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell. 2008 Sep 19;134(6):1042-54. doi: 10.1016/j.cell.2008.07.031. PMID:18805096 doi:http://dx.doi.org/10.1016/j.cell.2008.07.031
↑ Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762-7. PMID:7935836 doi:http://dx.doi.org/10.1038/371762a0
↑ Sekiyama N, Arthanari H, Papadopoulos E, Rodriguez-Mias RA, Wagner G, Leger-Abraham M. Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1. Proc Natl Acad Sci U S A. 2015 Jul 13. pii: 201512118. PMID:26170285 doi:http://dx.doi.org/10.1073/pnas.1512118112

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5bxv"

@@ Line 1: / Line 1: @@
 ==eIF4E complex==
 <StructureSection load='5bxv' size='340' side='right' caption='[[5bxv]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[5bxv]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BXV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BXV FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MGP:7-METHYL-GUANOSINE-5-TRIPHOSPHATE'>MGP</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5bxv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bxv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5bxv RCSB], [http://www.ebi.ac.uk/pdbsum/5bxv PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5bxv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bxv OCA], [http://pdbe.org/5bxv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bxv RCSB], [http://www.ebi.ac.uk/pdbsum/5bxv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bxv ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 5bxv" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

5bxv

From Proteopedia

Revision as of 13:22, 10 May 2017

eIF4E complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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