Journal
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
Volume 18, Issue -, Pages 696-704Publisher
ELSEVIER
DOI: 10.1016/j.csbj.2020.03.009
Keywords
Protein synthesis regulation; Translation initiation; Translation reinitiation; Translation recycling; Density regulated protein (DENR)
Funding
- NIH [GM022778]
- Sir Henry Wellcome Postdoctoral Fellowship, UK
- Anne McLaren Fellowship, University of Nottingham, UK
- Richards Center facility at Yale University
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The density regulated protein (DENR) forms a stable heterodimer with malignant T-cell-amplified sequence 1 (MCT-1). DENR-MCT-1 heterodimer then participates in regulation of non-canonical translation initiation and ribosomal recycling. The N-terminal domain of DENR interacts with MCT-1 and carries a classical tetrahedral zinc ion-binding site, which is crucial for the dimerization. DENR-MCT-1 binds the small (40S) ribosomal subunit through interactions between MCT-1 and helix h24 of the 18S rRNA, and through interactions between the C-terminal domain of DENR and helix h44 of the 18S rRNA. This later interaction occurs in the vicinity of the P site that is also the binding site for canonical translation initiation factor elF1, which plays the key role in initiation codon selection and scanning. Sequence homology modeling and a low-resolution crystal structure of the DENR-MCT-1 complex with the human 40S subunit suggests that the C-terminal domain of DENR and elF1 adopt a similar fold. Here we present the crystal structure of the C-terminal domain of DENR determined at 1.74 A resolution, which confirms its resemblance to elF1 and advances our understanding of the mechanism by which DENR-MCT-1 regulates non-canonical translation initiation and ribosomal recycling. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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