Structural basis for nematode eIF4E binding an m 2,2,7 G-Cap and its implications for translation initiation

Liu, Weizhi; Jankowska-Anyszka, Marzena; Piecyk, Karolina; Dickson, Laura B.; Wallace, Adam; Niedzwiecka, Anna; Stępiński, Janusz; Stolarski, Ryszard; Darżynkiewicz, Edward; Kieft, Jeffrey S.; Zhao, Rui; Jones, David N. M.; Davis, Richard E.

doi:10.1093/nar/gkr650

Cited by 41 publications

(41 citation statements)

References 54 publications

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“…In this study, eIF4E3 refers to the third subfamily of eIF4E proteins (15,16). Recent studies have appeared on Drosophila eIF4E3 (Dm4E3) (18) and Ascaris suum eIF4E3 (As4E3) (19); however, these proteins are not eIF4E3 subfamily members but actually belong to the eIF4E1 subfamily (third isoform of eIF4E1 in those species).…”

Section: Resultsmentioning

confidence: 99%

“…The backbone root-mean-square deviation (rmsd) for regular secondary structure elements is 1.86 Å for apo-eIF4E3 versus apo-eIF4E1 (8) and 1.60 Å for m 7 GDP-eIF4E3 versus m 7 GTP-eIF4E1 (25). An extra single turn α helix (denoted α0, residues [16][17][18][19][20] is seen in both eIF4E3 structures at the disordered N terminus (residues 1-30) that is not seen in any other eIF4E structure. We detected nuclear Overhauser effects (NOEs) between this helix and the α1 helix for the apo form, but not the m 7 GDP-bound form.…”

Section: Resultsmentioning

confidence: 99%

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eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

143

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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 π-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 growthpromoting 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.M etabolism of mRNA is a complex and highly regulated process dependent on the association of the methyl-7-guanosine (m 7 G) cap structure on the 5′ end of transcripts with appropriate proteins (1-3). In mammalian cells, the two major cap-binding proteins are the nuclear cap-binding complex (CBC) (4) and eukaryotic translation initiation factor 4E (eIF4E) (3). Specific cap recognition is key for the fate of transcripts and impacts processes such as mRNA processing and bulk mRNA export via the CBC or the nuclear export of specific transcripts as well as bulk translation by eIF4E (5). NMR and crystallographic studies reveal that m 7 G cap is specifically recognized by both the CBC and eIF4E via intercalation of the m 7 G cap moiety with the side chains of two aromatic residues, i.e., an aromatic sandwich (4, 6-9). This is an electrostatically driven process relying on the partial positive charge of the m 7 G cap and the negative π-electron clouds of the aromatic residues. The aromatic residues are completely conserved in these cap-binding proteins. This recognition motif is used almost exclusively by proteins that specifically bind the m 7 G cap including eIF4E, CBC, and vaccinia virus protein VP39 (4, 10).Dysregulation of cap-binding proteins can have striking physiological consequences. For instance through its cap-binding activity and subsequent effects on gene expression, eIF4E plays an important role in proliferation and survival (1, 3). Indeed, eIF4E is overexpressed in about 30% of human cancers and its overexpression is oncogenic in cell culture and animal models (2, 11). Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transform...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

143

View full text Add to dashboard Cite

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“…Detailed structural information is available on eIF4E from different species, in complex with cap analogs and with peptides derived from eIF4G and 4E-BPs. These peptides bind in a similar mode to a conserved surface on eIF4E, opposite and distal to the m 7 G cap-binding pocket (Marcotrigiano et al 1997(Marcotrigiano et al , 1999Matsuo et al 1997;Niedzwiecka et al 2002a;Gross et al 2003;Tomoo et al 2005;Volpon et al 2006Volpon et al , 2010Brown et al 2007Brown et al , 2009Monzingo et al 2007;Rosettani et al 2007;Ashby et al 2011;Liu et al 2011;Siddiqui et al 2012) (pdb id. : 3AM7).…”

mentioning

confidence: 99%

Crystal structure of a minimal eIF4E–Cup complex reveals a general mechanism of eIF4E regulation in translational repression

Kinkelin

Veith

Grünwald

et al. 2012

RNA

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Cup is an eIF4E-binding protein (4E-BP) that plays a central role in translational regulation of localized mRNAs during early Drosophila development. In particular, Cup is required for repressing translation of the maternally contributed oskar, nanos, and gurken mRNAs, all of which are essential for embryonic body axis determination. Here, we present the 2.8 Å resolution crystal structure of a minimal eIF4E-Cup assembly, consisting of the interacting regions of the two proteins. In the structure, two separate segments of Cup contact two orthogonal faces of eIF4E. The eIF4E-binding consensus motif of Cup (YXXXXLF) binds the convex side of eIF4E similarly to the consensus of other eIF4E-binding proteins, such as 4E-BPs and eIF4G. The second, noncanonical, eIF4E-binding site of Cup binds laterally and perpendicularly to the eIF4E b-sheet. Mutations of Cup at this binding site were shown to reduce binding to eIF4E and to promote the destabilization of the associated mRNA. Comparison with the binding mode of eIF4G to eIF4E suggests that Cup and eIF4G binding would be mutually exclusive at both binding sites. This shows how a common molecular surface of eIF4E might recognize different proteins acting at different times in the same pathway. The structure provides insight into the mechanism by which Cup disrupts eIF4E-eIF4G interaction and has broader implications for understanding the role of 4E-BPs in translational regulation.

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“…Nematode eIF4E readily translates TMG RNAs indicating this is a functional interaction. Consistent with the structural homology between nematode and human eIF4E, human eIF4E also binds the TMG cap albeit with a lower affinity than for the m 7 G cap 73 . Given the high concentrations of U snRNAs in the cell, the human eIF4E-TMG interaction may underlie some novel physiological role for eIF4E in mammals.…”

Section: Overviewmentioning

confidence: 65%

“…Crystal structures of nematode eIF4E-TMG complexes indicate that TMG binds similarly to the m 7 G cap 73 . Nematode eIF4E readily translates TMG RNAs indicating this is a functional interaction.…”

Section: Overviewmentioning

confidence: 97%

The eukaryotic translation initiation factor eIF4E wears a “cap” for many occasions

Borden

2016

Translation

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The eukaryotic translation initiation factor eIF4E plays important roles in controlling the composition of the proteome. Indeed, dysregulation of eIF4E is associated with poor prognosis cancers. The traditional view has been that eIF4E acts solely in translation. However, over the last ∼25 years, eIF4E was found in the nucleus where it acts in mRNA export and in the last ∼10 years, eIF4E was found in cytoplasmic processing bodies (P-bodies) where it functions in mRNA sequestration and stability. The common biochemical thread for these activities is the ability of eIF4E to bind the 7-methylguanosine cap on the 5′ end of mRNAs. Recently, the possibility that eIF4E directly binds some mRNA elements independently of the cap has also been raised. Importantly, the effects of eIF4E are not genome-wide with a subset of transcripts targeted depending on the presence of specific mRNA elements and context-dependent regulatory factors. Indeed, eIF4E governs RNA regulons through co-regulating the expression of groups of transcripts acting in the same biochemical pathways. In addition, studies over the past ∼15 years indicate that there are multiple strategies that regulatory factors employ to modulate eIF4E activities in context-dependent manners. This perspective focuses on these new findings and incorporates them into a broader model for eIF4E function.

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Structural basis for nematode eIF4E binding an m 2,2,7 G-Cap and its implications for translation initiation

Cited by 41 publications

References 54 publications

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Crystal structure of a minimal eIF4E–Cup complex reveals a general mechanism of eIF4E regulation in translational repression

The eukaryotic translation initiation factor eIF4E wears a “cap” for many occasions

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