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. 2011 Jun;39(11):4851-65.
doi: 10.1093/nar/gkr045. Epub 2011 Feb 8.

Common conformational changes induced in type 2 picornavirus IRESs by cognate trans-acting factors

Yingpu Yu  1 , Irina S Abaeva, Assen Marintchev, Tatyana V Pestova, Christopher U T Hellen
Affiliations

VSports在线直播 - Common conformational changes induced in type 2 picornavirus IRESs by cognate trans-acting factors

Yingpu Yu et al. Nucleic Acids Res. 2011 Jun.

Abstract

Type 2 internal ribosomal entry sites (IRESs) of encephalomyocarditis virus (EMCV), foot-and-mouth disease virus (FMDV) and other picornaviruses comprise five major domains H-L. Initiation of translation on these IRESs begins with specific binding of the central domain of initiation factor, eIF4G to the J-K domains, which is stimulated by eIF4A. eIF4G/eIF4A then restructure the region of ribosomal attachment on the IRES and promote recruitment of ribosomal 43S pre-initiation complexes. In addition to canonical translation factors, type 2 IRESs also require IRES trans-acting factors (ITAFs) that are hypothesized to stabilize the optimal IRES conformation that supports efficient ribosomal recruitment: the EMCV IRES is stimulated by pyrimidine tract binding protein (PTB), whereas the FMDV IRES requires PTB and ITAF(45). To test this hypothesis, we assessed the effect of ITAFs on the conformations of EMCV and FMDV IRESs by comparing their influence on hydroxyl radical cleavage of these IRESs from the central domain of eIF4G. The observed changes in cleavage patterns suggest that cognate ITAFs promote similar conformational changes that are consistent with adoption by the IRESs of comparable, more compact structures, in which domain J undergoes local conformational changes and is brought into closer proximity to the base of domain I. VSports手机版.

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Figure 1.
Figure 1.
Influence of nPTB on hydroxyl radical cleavage of the EMCV IRES in IRES/eIF4Gm/eIF4A complexes from Fe(II)-tethered eIF4Gm. (A) Ribbon diagram of the HEAT-1 domain of eIF4G (PDB: 1hu3), with spheres indicating newly introduced cysteines. (B–D) Primer extension analysis of hydroxyl radical cleavage of the IRES from Fe(II) tethered eIF4Gm in IRES/eIF4Gm/eIF4A complexes in the presence/absence of nPTB. Lanes C, T, A, G depict the corresponding EMCV sequence. IRES domains and nucleotides are indicated on the left of each panel, and cleavage sites are shown on the right; boxed numbers indicate sites at which nPTB enhanced cleavage.
Figure 2.
Figure 2.
Sites of hydroxyl radical cleavage in EMCV and FMDV IRESs from Fe(II)-tethered eIF4Gm in IRES/eIF4Gm/eIF4A complexes influenced by cognate ITAFs mapped onto the secondary structure of IRESs. Sites of hydroxyl radical cleavage from positions on eIF4Gm mapped onto the secondary structures of (A and B) the EMCV IRES and (C and D) the FMDV IRES (GenBank accession no. X00871). Models in panels B and D show only those sites at which cleavage was enhanced by nPTB or ITAF45. Nucleotide numbering of the EMCV IRES and nomenclature of IRES domains are as in (ref. 37). Cleavage sites are show in colors that match the colors of corresponding spheres in Figure 1A. Sites of strong cleavage are indicated by thick edging.
Figure 3.
Figure 3.
Influence of nPTB and ITAF45 on hydroxyl radical cleavage of the FMDV IRES in IRES/eIF4Gm/eIF4A complexes from Fe(II)-tethered eIF4Gm. (A) Ribbon diagram of the HEAT-1 domain of eIF4Gm, with spheres indicating newly introduced cysteines. (B–E) Primer extension analysis of hydroxyl radical cleavage of the IRES from Fe(II)-tethered eIF4Gm in IRES/eIF4Gm/eIF4A complexes in the presence/absence of nPTB and ITAF45. Lanes C, T, A, G depict the corresponding FMDV sequence. IRES domains and nucleotides are indicated on the left of each panel, and cleavage sites are shown on the right; boxed numbers indicate sites at which cleavage was enhanced by nPTB and ITAF45.
Figure 4.
Figure 4.
Comparison of changes induced by ITAFs and by 43S complexes in the pattern of hydroxyl radical cleavage of EMCV and FMDV IRESs from Fe(II) tethered eIF4Gm. Primer extension analysis of hydroxyl radical cleavage of (A–D) the EMCV IRES and (E–G) the FMDV IRES from Fe(II)-tethered eIF4Gm in IRES/eIF4Gm/eIF4A complexes in the presence of nPTB, ITAF45 or 43S complexes, as indicated. Lanes C, T, A, G depict corresponding EMCV and FMDV sequences. IRES nucleotides are indicated on the left of each panel; positions of cleaved nucleotides on the right are annotated to indicate sites of enhanced cleavage (solid boxes) and reduced cleavage (dashed box).
Figure 5.
Figure 5.
Hydroxyl radical cleavage of EMCV and FMDV IRESs from eIF4A in IRES/eIF4Gm/eIF4A ternary complexes. (A) Ribbon diagram of eIF4A in the closed ATP/RNA-bound conformation (PDB: 3EX7), with spheres indicating newly introduced cysteines. Primer extension analysis of hydroxyl radical cleavage of (B and C) the EMCV IRES and (D and E) the FMDV IRES from Fe(II)-tethered eIF4A in IRES/eIF4Gm/eIF4A complexes in the presence/absence of eIF4B, nPTB/ITAF45, ATP and adenosine 5′-[β,γ-imido] triphosphate (AMPPNP), as indicated. Lanes C, T, A, G depict corresponding EMCV and FMDV sequences. IRES nucleotides are indicated on the left of each panel, and cleavage sites are shown on the right. (F) Sites of hydroxyl radical cleavage from positions on eIF4A mapped onto the secondary structure of EMCV and FMDV IRESs. Cleavage sites are shown in colors that match the colors of corresponding spheres in (A).
Figure 6.
Figure 6.
Hydroxyl radical cleavage of 18S rRNA from eIF4Gm in eIF4Gm-associated 43S complexes. (A and B) Primer extension analysis of hydroxyl radical cleavage of 18S rRNA from Fe(II)-tethered eIF4Gm in eIF4Gm-bound 43S complexes. Lanes C, T, A, G depict the corresponding 18S rRNA sequence. 18S rRNA nucleotides are indicated on the left of each panel, and cleavage sites are shown on the right. (C) Cleavages in 18S rRNA from eIF4Gm (cyan spheres) mapped onto the crystal structure of the yeast 80S ribosome (31). 18S rRNA and ribosomal proteins are shown as grey and blue ribbons. ES6 is colored orange and helices within it are numbered. The radius of the spheres is proportional to the efficiency of cleavage.
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