4B6V: The Third Member of the Eif4e Family Represses Gene Expression VIA a Novel Mode of Recognition of the Methyl-7 Guanosine CAP Moiety

Recognition of the methyl-7-guanosine (m(7)G) cap structure on mRNA is an essential feature of mRNA metabolism and thus gene expression. Eukaryotic translation initiation factor 4E (eIF4E) promotes translation, mRNA export, proliferation, and oncogenic transformation dependent on this cap-binding activity. eIF4E-cap recognition is mediated via complementary charge interactions of the positively charged m(7)G cap between the negative pi-electron clouds from two aromatic residues. Here, we demonstrate that a variant subfamily, eIF4E3, specifically binds the m(7)G cap in the absence of an aromatic sandwich, using instead a different spatial arrangement of residues to provide the necessary electrostatic and van der Waals contacts. Contacts are much more extensive between eIF4E3-cap than other family members. Structural analyses of other cap-binding proteins indicate this recognition mode is atypical. We demonstrate that eIF4E3 relies on this cap-binding activity to act as a tumor suppressor, competing with the growth-promoting functions of eIF4E. In fact, reduced eIF4E3 in high eIF4E cancers suggests that eIF4E3 underlies a clinically relevant inhibitory mechanism that is lost in some malignancies. Taken together, there is more structural plasticity in cap recognition than previously thought, and this is physiologically relevant.
PDB ID: 4B6VDownload
MMDB ID: 107898
PDB Deposition Date: 2012/8/15
Updated in MMDB: 2016/05 
Experimental Method:
solution nmr
Source Organism:
Similar Structures:
Biological Unit for 4B6V: monomeric; determined by software (PISA)
Molecular Components in 4B6V
Label Count Molecule
Protein (1 molecule)
Eukaryotic Translation Initiation Factor 4E Type 3
Molecule annotation
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Citing MMDB