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Structural Basis for Translational Surveillance by the Large Ribosomal Subunit-Associated Protein Quality Control Complex

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Structural Basis for Translational Surveillance by the Large Ribosomal Subunit-Associated Protein Quality Control Complex Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex Dmitry Lyumkisa,1,2, Dario Oliveira dos Passosb,1,2, Erich B. Taharab, Kristofor Webbc, Eric J. Bennettc, Staal Vinterbod, Clinton S. Pottera, Bridget Carraghera,3, and Claudio A. P. Joazeirob,3 aNational Resource for Automated Molecular Microscopy and Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; bDepartment of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; and Divisions of cBiological Sciences, Section of Cell and Developmental Biology, and dBiomedical Informatics, University of California, San Diego, La Jolla, CA 92093 Edited by David DeRosier, Brandeis University, Waltham, MA, and approved September 29, 2014 (received for review July 23, 2014) All organisms have evolved mechanisms to manage the stalling of then results in the recruitment of the AAA ATPase Cdc48/p97/ ribosomes upon translation of aberrant mRNA. In eukaryotes, the VCP. This recruitment also requires Rqc1 and Tae2, and is large ribosomal subunit-associated quality control complex (RQC), followed by Cdc48-mediated nascent chain extraction and de- composed of the listerin/Ltn1 E3 ubiquitin ligase and cofactors, livery to the proteasome for degradation (7–9). mediates the ubiquitylation and extraction of ribosome-stalled Exactly how RQC recognizes stalled ribosomes and performs its nascent polypeptide chains for proteasomal degradation. How functions has not been understood, and the only structure available RQC recognizes stalled ribosomes and performs its functions has in this system is that of free Ltn1 at 40-Å resolution (10). To elu- not been understood. Using single-particle cryoelectron micros- cidate mechanisms underlying RQC function, we set out to solve copy, we have determined the structure of the RQC complex the structure of the endogenous complex purified from yeast. To reduce sample heterogeneity so as to facilitate structural charac- bound to stalled 60S ribosomal subunits. The structure establishes terization,RQCassemblywasblockedinapreubiquitylationstepby how Ltn1 associates with the large ribosomal subunit and properly using cells expressing endogenous Ltn1 with a deletion of the E3- positions its E3-catalytic RING domain to mediate nascent chain catalytic RING domain (Ltn1-ΔR). This Ltn1 mutant is competent ubiquitylation. The structure also reveals that a distinguishing for binding to 60S subunits but fails to ubiquitylate substrates (4), feature of stalled 60S particles is an exposed, nascent chain- thus preventing downstream events from being triggered. conjugated tRNA, and that the Tae2 subunit of RQC, which facilitates Ltn1 binding, is responsible for selective recognition of Results stalled 60S subunits. RQC components are engaged in interactions Purification and EM Processing of the RQC Complex. AFlagtag across a large span of the 60S subunit surface, connecting the added to the C terminus of the Ltn1-ΔR subunit enabled affinity ΔR tRNA in the peptidyl transferase center to the distally located purification of the complex, hereby referred to as RQC .Anti-Flag nascent chain tunnel exit. This work provides insights into a mech- immunoprecipitation (IP) of prefractionated extracts followed by BIOPHYSICS AND anism linking translation and protein degradation that targets COMPUTATIONAL BIOLOGY defective proteins immediately after synthesis, while ignoring na- Significance scent chains in normally translating ribosomes. All organisms have systems in place to ensure that aberrant na- Tae2/Nemf | translational surveillance | protein quality control | scent polypeptide chains are promptly dealt with before being cryo-EM | listerin/Ltn1 E3 ubiquitin ligase released from ribosomes and posing harm to the cell. The ribo- some-associated quality control complex (RQC), composed of the uring the canonical termination and recycling steps of Ltn1 E3 ubiquitin ligase catalytic subunit and cofactors, has be- Dtranslation, stop codon recognition triggers factor-mediated come a paradigm for understanding quality control in eukaryotes. hydrolysis of the nascent peptidyl-tRNA conjugate, nascent However, exactly how RQC functions has remained unknown. chain release, and ribosome splitting (1–3). Conversely, trans- Here, we determine the structure of the 60S subunit-bound RQC lation of aberrant mRNA, such as mRNA lacking stop codons complex. The data provide critical insights into how RQC is able to (“nonstop mRNA”), renders 80S ribosomes stalled with nascent selectively target aberrant nascent chains, while ignoring nascent polypeptides (1–3). Furthermore, “nonstop proteins” cannot be chains in normally translating ribosomes. Furthermore, the struc- corrected by quality control chaperones and have the potential to ture shows the architecture of a ribosome-bound E3 ligase poised interfere with cellular function (3, 4). Not surprisingly, defective to mark nascent chains for degradation. termination and recycling are under surveillance by a variety of mechanisms (1–3). In eukaryotes, “rescue factors” homologous Author contributions: D.L., D.O.d.P., C.S.P., B.C., and C.A.P.J. designed research; D.L., D.O.d.P., to termination factors promote dissociation of translationally E.B.T., K.W., E.J.B., and S.V. performed research; D.L., D.O.d.P., E.B.T., K.W., E.J.B., and S.V. contributed new reagents/analytic tools; D.L., D.O.d.P., E.B.T., K.W., E.J.B., S.V., C.S.P., B.C., halted ribosomes in a stop codon-independent manner (5). and C.A.P.J. analyzed data; and D.L., D.O.d.P., C.S.P., B.C., and C.A.P.J. wrote the paper. However, because rescue factors lack peptidyl-tRNA hydrolase The authors declare no conflict of interest. activity, their action results in nascent chains remaining stalled This article is a PNAS Direct Submission. on the released 60S subunit. Data deposition: EM maps have been deposited in the Electron Microscopy Data Ltn1 is the critical E3 ligase mediating ubiquitylation of ab- Bank (EMD-2797 and EMD-2798 for the RQC-delta-RING and RQC-delta-RING/Tae2D errant proteins that become stalled on ribosomes during trans- reconstructions, respectively). lation (4). Mutation of the Ltn1 mouse ortholog, listerin, causes 1D.L. and D.O.d.P. contributed equally to this work. neurodegeneration (6), suggesting an important function for this 2Present address: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, process. Ltn1 works together with several cofactors as part of the CA 92093. – ribosome-associated quality control complex (RQC) (7 9) and 3To whom correspondence may be addressed. Email: [email protected] or joazeiro@ appears to first associate with nascent chain-stalled 60S subunits scripps.edu. together with two proteins of unknown function, Tae2 and Rqc1 This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (7, 9). Ltn1-mediated ubiquitylation of the stalled polypeptide 1073/pnas.1413882111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1413882111 PNAS | November 11, 2014 | vol. 111 | no. 45 | 15981–15986 Downloaded by guest on September 29, 2021 elution with Flag peptide recovered, as expected, Ltn1, 60S alongside (Fig. 2 C and D). This attachment region has been ribosomal subunit proteins, Tae2, and Rqc1, according to both sil- previously implicated in the binding of other factors involved in ver staining of SDS/PAGE gels (Fig. S1) and mass spectrometry nascent chain metabolism (16). (MS) analyses (Dataset S1). This sample, containing both ribosomal Ltn1’s middle region, unlike the ends, exhibits no obvious di- and RQC components, was vitrified for imaging by single-particle rect contacts. Rather, this region, predicted to be composed of cryoelectron microscopy (cryo-EM). Individual raw particles of the a long stretch of HEAT- or ARM-type α-helical repeats (10), sample (Fig. S2A) were summed into homogeneous groups of class appears to function as a linker mediating communication be- averages (Fig. S2B). From these class averages and using a recently tween Ltn1’s ends bound to distal sites on the ribosome. This described method for generating ab initio 3D reconstructions from observation may explain the apparent lack of sequence conser- single-particle data (11), we computed an initial model that clearly vation of the middle region among Ltn1 orthologs (4) and why resembled the 60S ribosomal subunit (Fig. S2C), with strong the ENU-induced 13-aa internal deletion in the corresponding agreement between the reference-free class averages and the region of mouse listerin results in a hypomorphic allele and reprojections from the computed model (Fig. S2D). Taken to- neurodegeneration (6). gether, these results indicated that complexes with the 60S subunit were the primary constituent of the sample. Structural Basis for Ltn1’s Selective Binding to the 60S Ribosomal The initial model of the 60S subunit was further refined using Subunit. Ltn1 was found only in association with 60S ribosomal a conventional single-model refinement protocol to a nominal subunits in the samples analyzed, and there was no indication resolution of 8.5 Å (Fig. S3 A and B); the resolution is in part that it can bind to 80S ribosomes. This observation supports limited by the preferred particle orientation (Fig. S3C) and previous data showing that Ltn1 is predominantly found in the background from the thin carbon support. The local resolution 60S fraction of sucrose gradients (4), copurifies with 60S subunits
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