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Crystal Structure of the DENR-MCT-1 Complex Revealed Zinc-Binding Site Essential for Heterodimer Formation

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Crystal Structure of the DENR-MCT-1 Complex Revealed Zinc-Binding Site Essential for Heterodimer Formation Crystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation Ivan B. Lomakina,1, Sergey E. Dmitrievb, and Thomas A. Steitza,c,2 aDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114; bBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia; and cHoward Hughes Medical Institute, Yale University, New Haven, CT 06520-8114 Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved November 29, 2018 (received for review June 5, 2018) The density-regulated protein (DENR) and the malignant T cell- of the ribosomal complex with DENR-MCT-1 at 6-Åresolution amplified sequence 1 (MCT-1/MCTS1) oncoprotein support nonca- (13). It showed that the structure of the C-terminal domain of nonical translation initiation, promote translation reinitiation on a DENR (C-DENR) is similar to that of the canonical translation specific set of mRNAs with short upstream reading frames, and initiation factor 1 (eIF1), which controls the fidelity of trans- regulate ribosome recycling. DENR and MCT-1 form a heterodimer, lation initiation and scanning. Moreover, C-DENR binds the 40S which binds to the ribosome. We determined the crystal structure of ribosomal subunit at the same site as eIF1. These data suggest a the heterodimer formed by human MCT-1 and the N-terminal do- similar mechanism for DENR-MCT-1 and eIF1 in discriminating main of DENR at 2.0-Å resolution. The structure of the heterodimer the initiator tRNA in the P site of the 40S subunit, which is reveals atomic details of the mechanism of DENR and MCT-1 inter- crucial for translation initiation, reinitiation, and ribosomal action. Four conserved cysteine residues of DENR (C34, C37, C44, recycling (13, 17). Binding of the MCT-1 to the 40S subunit is C53) form a classical tetrahedral zinc ion-binding site, which pre- mutually exclusive with the binding of both eIF3a and 3b sub- serves the structure of the DENR’sMCT-1–binding interface that is units of eIF3, which suggests that DENR-MCT-1 may function essential for the dimerization. Substitution of all four cysteines by as the eIF3 sensor directing the posttermination 40S subunit alanine abolished a heterodimer formation. Our findings elucidate either for reinitiation (if eIF3 is bound) or recycling (if eIF3 is further the mechanism of regulation of DENR-MCT-1 activities in dissociated) (13). The function of DENR-MCT-1 in translation unconventional translation initiation, reinitiation, and recycling. is similar to that of the noncanonical translation initiation factor eIF2D (13, 15, 16, 18, 19). eIF2D is a single polypeptide, which protein synthesis regulation | translation initiation | translation shares domain architecture with DENR-MCT-1 (Fig. 1A). Re- reinitiation | translation recycling | zinc binding cent X-ray crystallography and cryo-electron microscopy (cryo- EM) studies have revealed that the C-terminal domains of both ranslation initiation is the most regulated step of the protein eIF2D and DENR have the same SUI1 (eIF1-like) fold and Tsynthesis. In eukaryotes, it is coordinated by more than a binding site on the 40S ribosomal subunit (13, 15, 19). N-terminal dozen initiation factors (eIF) consisting of more than 30 proteins domains of eIF2D and MCT-1 also have a similar fold and interact compared with only three IFs in bacteria. Initiation factors facil- with the 40S subunit at the same site (13, 15, 20). Moreover, Met itate selection of the initiator tRNA (tRNAi ), the recruitment structure of the human 40S ribosomal subunit complex with eIF2D, of mRNA, and the scanning of its 5′ untranslated region (UTR) to the initiator tRNA, and the hepatitis C virus internal ribosome entry locate the start codon (AUG) of the main ORF, and, finally, the joining of the small (40S) and large (60S) ribosomal subunits, Significance which results in the formation of the 80S ribosome primed for a ′ protein synthesis (1, 2). Recent data have revealed that many 5 Protein synthesis or mRNA translation by ribosomes is essen- UTRs may have one or more AUG codons upstream of the main tial for the cell’s survival. A multitude of human diseases are start codon. This may lead to a synthesis of peptides encoded by the direct result of disruption of translation, specifically at the the upstream ORFs (uORFs) or a different isoform of the main initiation step. The density-regulated protein (DENR) and the protein if the upstream AUG is in-frame with the main AUG. malignant T cell-amplified sequence 1 (MCT-1/MCTS1) onco- uORFs may inhibit translation of the main ORF or regulate it by protein support noncanonical translation initiation, reinitia- reinitiation (3, 4). Reinitiation may occur if the 40S ribosomal tion, and ribosome recycling linked to cancer, neurological subunit does not dissociate from mRNA after translation termi- disorders, and viral infections. Here, we present the crystal nation, i.e., is not recycled and is able to reach the nearest AUG. structure of a DENR-MCT-1 heterodimer, which reveals atomic Canonical translation initiation factors (eIF1, eIF1A, eIF2, eIF3, details of DENR and MCT-1 interactions that are crucial for eIF4F) are likely involved in this process; however, the exact understanding their function in translation. Our results provide mechanism of reinitiation is still not well understood (5, 6). foundation for the future research of the mechanism of regu- The density-regulated protein (DENR) and the malignant lation of noncanonical protein synthesis and may potentially T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein were be used for antiviral, anticancer, and neurological drug design. recently shown to promote reinitiation after short uORFs of a specific set of mRNAs, which are involved in cell proliferation Author contributions: I.B.L. and T.A.S. designed research; I.B.L. performed research; I.B.L., and signaling in flies (7). The oncoprotein MCT-1 was identified S.E.D., and T.A.S. analyzed data; and I.B.L., S.E.D., and T.A.S. wrote the paper. in human T cell leukemia and lymphoma, and it has been as- The authors declare no conflict of interest. sociated with increased cell proliferation and genome instability This article is a PNAS Direct Submission. (8, 9). Synthesis of DENR protein is up-regulated with increasing Published under the PNAS license. cell density, and it is also overexpressed in breast and ovarian Data deposition: The crystallography, atomic coordinates, and structure factors have been cancers (10, 11). DENR forms a heterodimer with MCT-1, both deposited in the Protein Data Bank, www.wwpdb.org (PDB ID 6MS4). in vivo and in vitro, and this heterodimerization is essential for 1To whom correspondence should be addressed. Email: [email protected]. the DENR-MCT-1 activity in mRNA translation initiation, 2Deceased October 9, 2018. reinitiation, and the ribosome recycling (12–16). Recently, we This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. have characterized the DENR-MCT-1 interaction with the hu- 1073/pnas.1809688116/-/DCSupplemental. man 40S ribosomal subunit by determining the crystal structure Published online December 24, 2018. 528–533 | PNAS | January 8, 2019 | vol. 116 | no. 2 www.pnas.org/cgi/doi/10.1073/pnas.1809688116 Downloaded by guest on September 29, 2021 A 1 93 173 383 470 491 584 D DUF1947 PUA WH SWIB/MDM2 SUI1 eIF2D MCT-1 DUF1947 PUA SUI1 DENR 1 92 181 1 93 106 198 MCT-1 N-DENR PUA B Zn 1 69 MW D11-98+M eIF1+M D110-198+M D26-198+M T7-tag M, no kDa D10-198+M D51-198+M 62- α4 49- α3 38- 10-198 26-198 51-198 DUF1947 28- MCT-1 110-198 17- 11-98 N-DENR 26 (26-98) 14- 1 2 3 4 5 6 7 C E 69 PUA BIOCHEMISTRY D26-98+M D26-98+M D11-98+M M, reference D26-98 C37Y+M, soluble C37Y+M, insoluble cDENR+M D26-98C2A+M C37Y+M, flowthrough C37Y+M, eluate 62- N-DENR 49- 26 38- DUF1947 28- MCT-1 17- 11-98 26-98 14- C 1 2 3 4 5 6 7 8 9 10 11 Fig. 1. Overview of the DENR-MCT-1 heterodimer structure. (A) Domain structure of eIF2D, MCT-1, and DENR. Residues for the borders of the domains are numbered. (B)T7•Tag antibody agarose-binding assay. T7-tagged DENR (marked as D) deletion mutants were immobilized on T7•Tag antibody agarose in the presence of BSA and MCT-1 (marked as M) and washed with the buffer, and the bound proteins were analyzed by polyacrylamide gel electrophoresis. T7-tagged eIF1 (lane 1) was used as a negative control. DENR positions are marked by black arrows with numbers, which correspond to the amino acid residue numbers of DENR. (C)AsinB, C-DENR was used as a negative control. Coexpressed with MCT-1 and eluted from the Ni-NTA agarose N-DENR (lane 6), N-DENR (4Cys-to-Ala mutant, lane 7) and N-DENR (C37Y, lane 11). Soluble (lane 8), insoluble (lane 9), and Ni-NTA agarose column flow-through proteins (lane 10) of coexpressed N- + DENR(C37Y). (D) Cartoon representation of the crystal structure of the human DENR-MCT-1 heterodimer. DENR shown in coral, MCT-1 in green, and Zn2 ion in + gray. The PUA and DUF1947 domains of MCT-1 are marked. The anomalous difference Fourier map (blue mesh) around the Zn2 ion (unique outstanding peak, σ = 20.8) is contoured at σ = 13. (E) Superposed (by DUF1947) main chains of DENR-MCT-1: DENR-MST-1 presented in this paper (colored as in B), MCT-1 alone (PDB ID 3R90, red), PDB ID 5ONS (brown, blue), on ribosome (PDB ID 5VYC, gray), MCT-1-like domain of eIF2D on ribosome (PDB ID 5OA3, violet).
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