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Research Collection Research Collection Journal Article The complete structure of the large subunit of the mammalian mitochondrial ribosome Author(s): Greber, Basil J.; Boehringer, Daniel; Leibundgut, Marc; Bieri, Philipp; Leitner, Alexander; Schmitz, Nikolaus; Aebersold, Ruedi; Ban, Nenad Publication Date: 2014-10-01 Permanent Link: https://doi.org/10.3929/ethz-b-000093239 Originally published in: Nature 515(7526), http://doi.org/10.1038/nature13895 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Supplementary Online Material for The Complete Structure of the Large Subunit of the Mammalian Mitoribosome Basil J. Greber*, Daniel Boehringer*, Marc Leibundgut*, Philipp Bieri, Alexander Leitner, Nikolaus Schmitz, Ruedi Aebersold, and Nenad Ban† * These authors contributed equally to this work † Correspondence to: [email protected] (NB) This file contains: Supplementary Discussion Supplementary Table 1 Supplementary Information References 59-69 Provided in a dedicated spreadsheet file: Supplementary Table 2 Supplementary Discussion Identification of mL65 (MRPS30) and mL66 (MRPS18A) as 39S Subunit Components The mammalian mitochondrial ribosomal specific proteins mL37 and mL65 (MRPS30; previously termed PDCD9 59 or p52 60) are homologous to each other (Extended Data Fig. 5b, c) and dimerize via an extensive interface (1430 Å2; computed with PDBePISA 61). The presence of mL65 (MRPS30) on the 39S subunit is unexpected, as it was initially identified as a protein of the small mitoribosomal subunit 59. However, our assignment based on the inspection of the well-resolved amino acid side chains in the cryo-EM density was unambiguous (Extended Data Fig. 5d) and further independently confirmed by CX-MS crosslinks between mL65 (MRPS30) and mL37, as well as crosslinks between mL65 (MRPS30) and other mitoribosomal proteins in its immediate vicinity (Extended Data Fig. 5e, f; Extended Data Table 1). Interestingly, mutations leading to altered expression of mL65 (MRPS30) have been linked to breast cancer susceptibility 62. Whether these effects are connected to the mitoribosomal functions of mL65 (MRPS30) or to an extra- ribosomal role of this protein remains to be established. Three bS18 homologs (A, B, and C) occur in mammalian mitochondria, and all of them were assigned as small subunit proteins based on mass- spectrometry experiments 63. However, analysis of a region of density near the L7/L12 stalk revealed a bS18-like fold, and the corresponding protein was unambiguously identified as mL66 (MRPS18A) based on side chain features and total chain length (Extended Data Fig. 5g, h). Therefore, mL66 (MRPS18A) has likely evolved to become a large subunit protein, while mS18B and mS18C may constitute components of the small mitoribosomal subunit. mL66 (MRPS18A) binds to the L7/L12 stalk base (Extended Data Figs. 5g, l) and may help stabilizing the rRNA in this region, as the rRNA connecting the L7/L12 stalk base to the subunit body has been remodeled compared to bacterial ribosomes. Given their previous assignment as small subunit proteins, we sought to establish whether mL65 (MRPS30) and mL66 (MRPS18A) occur in both the small and large mitoribosomal subunits or in the large subunit only. A label- free semi-quantitative analysis 45,46 of our mass spectrometry data indicates that both mL65 (MRPS30) and mL66 (MRPS18A) are present in equal abundance relative to most other mitoribosomal proteins, suggesting that their copy number in the 55S mitoribosome is one (Extended Data Fig. 5i). We therefore suggest the names mL65 and mL66 for MRPS30 and MRPS18A, respectively, to indicate that they are components of the 39S subunit. Insights into Mitoribosome Evolution We previously showed that mL44 and mL39, two mitoribosomal proteins with homology to RNA binding enzymes - RNase III 64 and threonyl-tRNA synthetase 65, respectively - bind to the 39S subunit via protein-protein interactions, leaving their former RNA-binding surfaces solvent-exposed 6 (Extended Data Fig. 9a). mL44 also occurs in the yeast 54S mitoribosomal large subunit, where it binds to an rRNA expansion segment that is located nearby, together with mL57, a second RNase III homolog 5 (Extended Data Fig. 9b). This suggests that during evolution of the mitoribosome, both mL39 and mL44 initially bound to rRNA expansion segments and have been retained in the 39S subunit even though these rRNA segments have been lost in mammals (Extended Data Fig. 9c). This indicates that early in mitoribosomal evolution, expansion segments in the rRNA evolved, and novel proteins were recruited, resulting in expanded mitoribosomes, as exemplified by the yeast mitoribosome. Subsequently, during the evolution of higher eukaryotes, and mammals in particular, the mitoribosomal rRNAs were dramatically shortened, while previously acquired mitoribosomal specific proteins were retained, and the recruitment and expansion of mitoribosomal proteins continued, possibly in part to architecturally compensate for the loss of rRNA 6,66,67. The reduction of the mitochondrial genome may also have led to the dual use of a tRNA as an adaptor molecule during mitochondrial protein synthesis and as a structural component of the mitoribosome. Supplementary Table 1 | Summary of components in the 39S subunit model. See online methods section for details of the protein naming convention used 10. Protein*/ Old Chain Full size† Modeled Sequence Structural Comments RNA name* ID (residues) residues accession code homologs uL1m MRPL1 - 329 - AK349766.1 uL1 not visible uL2m MRPL2 D 306 61-300 NP_001171996.1 uL2 uL3m MRPL3 E 348 42-348 AY609899.1 uL3 uL4m MRPL4 F 294 45-294 XP_003123269.2 uL4 bL9m MRPL9 I 268 53-150 XP_003355223.1 bL9 Zn2+ binding together uL10m MRPL10 J 262 29-196 XP_003131579.1 uL10 with mL66 uL11m MRPL11 K 192 17-158 XP_003122536.1 uL11 bL7m/ bL7/ MRPL12 - 198 - AK234571.1 not visible bL12m bL12 uL13m MRPL13 N 178 2-178 NP_001230344.1 uL13 uL14m MRPL14 O 145 31-145 XP_001929596.1 uL14 uL15m MRPL15 P 296 9-296 NP_001230457.1 uL15 uL16m MRPL16 Q 251 31-251 NP_001231896.1 uL16 bL17m MRPL17 R 169 9-161 NP_001231309.1 bL17 uL18m MRPL18 S 180 38-180 XP_001928391.1 uL18 bL19m MRPL19 T 292 69-292 XP_003354803.1 bL19 bL20m MRPL20 U 149 10-149 XP_003127555.3 bL20 bL21m MRPL21 V 209 55-209 AY610123.1 bL21 uL22m MRPL22 W 210 45-210 AK392578.1 uL22 2-116, uL23m MRPL23 X 150 AK392218.1 uL23 132-150 uL24m MRPL24 Y 216 13-216 NP_001231376.1 uL24 bL27m MRPL27 0 148 35-148 XP_003131628.3 bL27 bL28m MRPL28 1 256 2-245 XP_003124744.1 bL28 uL29m MRPL47 2 252 66-243 XP_003132595.1 uL29 uL30m MRPL30 3 161 35-152 XP_003354768.1 uL30 bL31m MRPL55 4 126 35-79 XP_005661204.1 bL31 79-188, 2+ bL32m MRPL32 5 188 AK343710.1 bL32 Zn binding Zn 500 bL33m MRPL33 6 65 13-60 XP_003125332.1 bL33 bL34m MRPL34 7 95 50-95 AW415886.1 bL34 bL35m MRPL35 8 188 94-188 XP_003124984.1 bL35 63-100, 2+ bL36m MRPL36 9 100 AK392116.1 bL36 Zn binding Zn 500 restriction homology to and dimerization mL37 MRPL37 a 423 30-422 AK237653.1 endonuclease-like|| with mL65 mL38 MRPL38 b 380 27-380 XP_003131236.1 PEBP-like§ tRNA synthetase domain mL39 MRPL39 c 334 30-324 XP_003132793.4 like§ mL40 MRPL40 d 206 83-181 NP_001230488.1 yeast mL40 extended structure mL41 MRPL41 e 135 15-135 AW787117.1 yeast mL41 extended structure extended structure, mL42 MRPL42 f 142 35-142 AY609966.1 novel fold residues 77-100 built as UNK‡ Supplementary Table 1 (continued) Protein*/ Old Chain Full size† Modeled Sequence Structural Comments RNA name* ID (residues) residues accession code homologs* mL43 MRPL43 g 159 2-149 XP_003483589.1 thioredoxin like§ RNase III domain- mL44 MRPL44 h 332 31-319 NP_001230334.1 like§ mL45 MRPL45 i 312 56-297 AK232067.1 cystatin-like§ 43-104, 116- mL46 MRPL46 j 279 XP_003121908.1 nudix hydrolase§ 217, 227-279 48-66, 77- ferredoxin- mL48 MRPL48 k 212 AK391730.1 138, 144-193 like§ mL49 MRPL49 l 166 34-166 NP_001231942.1 eIF1-like§ mL50 MRPL50 m 159 51-159 XP_003122091.1 ACP-like§ STAR protein 2-helical motif mL51 MRPL51 n 128 32-128 EW306587.2 dimerization surrounded by domain|| rRNA extended mL52 MRPL52 o 124 23-116 NP_001172080.1 novel fold structure mL53 MRPL53 p 112 2-98 XP_003125037.1 thioredoxin-like§ only C-terminal mL54 MRPL54 q 138 102-138 XP_003123104.1 not determined helix visible - MRPL56 - 556 - NP_001230291.1 not detected residues 164- MRPL58 38-85, peptidyl-tRNA mL62 u 205 NP_001231224.1 173 built as (ICT1) 93-195 hydrolase§ UNK‡ MRPL57 homeo-domain- mL63 t 102 9-102 AK347505.1 (MRP63) like§ extended structure, MRPL59 mL64 v 222 25-155 XP_003123387.1 novel fold residues 144- (CRIF1) 155 built as UNK‡ restriction homology to and mL65 MRPS30 w 433 40-426 AK236026.1 endonuclease- dimerization with like|| mL37 Zn2+ binding 35-196, mL66 MRPS18A x 196 FD604770.1 bS18 together with Zn 500 uL10 unassigned secondary 9-36, 99- z - structure 106, 201-211 elements, built as UNK‡ 1-18, 25-140, 16S 146-886, 889-906, A 1569 AJ002189.1 rRNA 909-1089, 1122-1211, 1220-1569 mitochondrial tRNA replacing the 5S rRNA, CP tRNA B 73 1-15, 23-53, 58-73 bases deposited as purines and pyrimidines P-site CCA-3’ end of P- C 74-76 tRNA site tRNA A-site CCA-3’ end of A- Z 74-76 tRNA site tRNA * Nomenclature according to the ribosomal protein gene database 68 and used for our previous 4.9 Å-structure of the 39S subunit 6. † Full-length protein sequences including putative mitochondrial targeting peptides. ‡ Unassigned residues were modeled as poly-serine and deposited as UNK. § Fold predicted by the Phyre2 protein fold recognition server 50.
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