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The Leishmania PABP1–eIF4E4 interface : a novel 5′–3′ interaction architecture for trans-spliced mRNAs
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Santos Rodrigues, Fabio Henrique dos, Firczuk, Helena , Breeze, Alexander L., Cameron, Alexander, Walko, Martin, Wilson, Andrew J, Zanchin , Nilson I.T. and McCarthy, John E. G. (2019) The Leishmania PABP1–eIF4E4 interface : a novel 5′–3′ interaction architecture for trans-spliced mRNAs. Nucleic Acids Research, 47 (3). pp. 1493-1504. doi:10.1093/nar/gky1187 ISSN 0305-1048.
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Official URL: http://dx.doi.org/10.1093/nar/gky1187
Abstract
Trans-splicing of trypanosomatid polycistronic transcripts produces polyadenylated monocistronic mRNAs modified to form the 5′ cap4 structure (m7Gpppm36,6,2′Apm2′Apm2′Cpm23,2′U). NMR and X-ray crystallography reveal that Leishmania has a unique type of N-terminally-extended cap-binding protein (eIF4E4) that binds via a PAM2 motif to PABP1. This relies on the interactions of a combination of polar and charged amino acid side-chains together with multiple hydrophobic interactions, and underpins a novel architecture in the Leishmania cap4-binding translation factor complex. Measurements using microscale thermophoresis, fluorescence anisotropy and surface plasmon resonance characterize the key interactions driving assembly of the Leishmania translation initiation complex. We demonstrate that this complex can accommodate Leishmania eIF4G3 which, unlike the standard eukaryotic initiation complex paradigm, binds tightly to eIF4E4, but not to PABP1. Thus, in Leishmania, the chain of interactions 5′cap4-eIF4E4–PABP1-poly(A) bridges the mRNA 5′ and 3′ ends. Exceptionally, therefore, by binding tightly to two protein ligands and to the mRNA 5′ cap4 structure, the trypanosomatid N-terminally extended form of eIF4E acts as the core molecular scaffold for the mRNA-cap-binding complex. Finally, the eIF4E4 N-terminal extension is an intrinsically disordered region that transitions to a partly folded form upon binding to PABP1, whereby this interaction is not modulated by poly(A) binding to PABP1.
Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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Subjects: | Q Science > QL Zoology Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Leishmania -- Physiological aspects, Messenger RNA | |||||||||||||||||||||||||||||||||
Journal or Publication Title: | Nucleic Acids Research | |||||||||||||||||||||||||||||||||
Publisher: | Oxford University Press | |||||||||||||||||||||||||||||||||
ISSN: | 0305-1048 | |||||||||||||||||||||||||||||||||
Official Date: | 20 February 2019 | |||||||||||||||||||||||||||||||||
Dates: |
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Volume: | 47 | |||||||||||||||||||||||||||||||||
Number: | 3 | |||||||||||||||||||||||||||||||||
Page Range: | pp. 1493-1504 | |||||||||||||||||||||||||||||||||
DOI: | 10.1093/nar/gky1187 | |||||||||||||||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||||||||||||||
Date of first compliant deposit: | 27 November 2018 | |||||||||||||||||||||||||||||||||
Date of first compliant Open Access: | 27 November 2018 | |||||||||||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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