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Cryo-EM Structure of Catalytic Ribonucleoprotein Complex Rnase MRP

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Cryo-EM Structure of Catalytic Ribonucleoprotein Complex Rnase MRP ARTICLE https://doi.org/10.1038/s41467-020-17308-z OPEN Cryo-EM structure of catalytic ribonucleoprotein complex RNase MRP Anna Perederina1,DiLi1, Hyunwook Lee1, Carol Bator1, Igor Berezin1, Susan L. Hafenstein1,2 & ✉ Andrey S. Krasilnikov 1,3 RNase MRP is an essential eukaryotic ribonucleoprotein complex involved in the maturation of rRNA and the regulation of the cell cycle. RNase MRP is related to the ribozyme-based 1234567890():,; RNase P, but it has evolved to have distinct cellular roles. We report a cryo-EM structure of the S. cerevisiae RNase MRP holoenzyme solved to 3.0 Å. We describe the structure of this 450 kDa complex, interactions between its components, and the organization of its catalytic RNA. We show that some of the RNase MRP proteins shared with RNase P undergo an unexpected RNA-driven remodeling that allows them to bind to divergent RNAs. Further, we reveal how this RNA-driven protein remodeling, acting together with the introduction of new auxiliary elements, results in the functional diversification of RNase MRP and its progenitor, RNase P, and demonstrate structural underpinnings of the acquisition of new functions by catalytic RNPs. 1 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, 16802 PA, USA. 2 Department of Medicine, Pennsylvania ✉ State University, Hershey, 17033 PA, USA. 3 Center for RNA Biology, Pennsylvania State University, University Park, 16802 PA, USA. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:3474 | https://doi.org/10.1038/s41467-020-17308-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17308-z ibonuclease (RNase) MRP, a site-specific endoribonuclease, RNases P have been determined21,22. S. cerevisiae RNase MRP is a ribonucleoprotein complex (RNP) comprising a cata- and RNase P share eight proteins (Pop1, Pop3, Pop4, Pop5, Pop6, R 23 lytic RNA moiety and multiple (ten in Saccharomyces cer- Pop7, Pop8, and Rpp1 (two copies)); RNase MRP protein Snm1 evisiae) protein components1–4. RNase MRP is an essential has a homolog in RNase P (Rpr2), while Rmp124 is found only in eukaryotic enzyme that has been found in practically all eukar- RNase MRP. Shared proteins bind to both C- and S- yotes analyzed5. RNase MRP is localized to the nucleolus and, domains21,25,26. Yeast RNase MRP proteins Pop1, Pop3, Pop4, transiently, to the cytoplasm3. Known RNase MRP functions Pop5, Pop6, Pop7, Pop8 have homologs in human RNase include its participation in the maturation of rRNA and in the P3,4,18,22, while Pop3, Pop4, Pop5, and Rpp1 have homologs in metabolism of specific mRNAs involved in the regulation of the archaeal RNases P3,4,27. cell cycle6–13. Defects in RNase MRP result in a range of pleio- RNase MRP proteins Pop1, Pop6, Pop7 are also an essential tropic developmental disorders in humans14. part of yeast telomerase, where they are involved in the locali- RNase MRP is evolutionarily related to RNase P, a ribozyme- zation of the enzyme and form a structural module that stabilizes based RNP primarily involved in the maturation of tRNA15–17. the binding of telomerase components Est1 and Est228,29. RNase MRP appears to have split from the RNase P lineage early Here, we report a cryo-EM structure of the S. cerevisiae RNase in the evolution of eukaryotes, acquiring distinct substrate spe- MRP holoenzyme solved to a nominal resolution of 3.0 Å. We cificity and cellular functions5,18,19. reveal the overall architecture of the RNP, the structural organi- The catalytic (C-) domain of RNase MRP RNA (Fig. 1a) has zation of its catalytic RNA moiety, the substrate binding pocket of the secondary structure resembling that of the C-domain of the enzyme, and interactions between RNase MRP components. RNase P (Fig. 1b) and includes elements forming a highly con- Further, we compare the structure of RNase MRP to the structure served catalytic core3–5. The specificity (S-) domain of RNase of the progenitor RNP, eukaryotic RNase P. We show that, sur- MRP RNA does not have any apparent similarities with the S- prisingly, several of the proteins shared by RNase MRP and domain of RNase P (Fig. 1a, b). Crosslinking studies20 indicate RNase P undergo RNA-driven structural remodeling, allowing the involvement of the RNase MRP S-domain in substrate the same proteins to function in distinct structural contexts. We recognition. demonstrate that while the structure of the catalytic center of Most of the RNase MRP protein components are also found in RNase MRP is practically identical to that of RNase P, the eukaryotic RNase P2; the structures of S. cerevisiae and human topology of the substrate binding pocket of RNase MRP diverges a 205 b 230 200 210 P12 220 P7 195 S-domain 240 S-domain 215 CR-II P6 180 210 175 CR-III 170 190 220 J7/9 C-domain 250 C-domain 180 225 P9 235 165 230 240 P9 J6/7 200 P10/11 100 145 245 170 190 95 255 250 160 P7 270 280 150 160 260 140 155 105 J8/9 P15 110 90 L5 260 110 P8 150 300 290 135 120 115 P4 125 P15 130 P5 P8 120 85 CR-IV P8* P4 90 310 70 265 140 130 60 65 75 55 80 80 70 CR-IV 45 P3 60 35 50 30 P3 40 50 270 285 30 25 20 P19 280 40 20 P19 P2 320 330 290 1 5 10 275 P2 5 15 295 1 10 315 CR-Va 335 330 325 300 305 340 3 340 320 310 P1 360 P4 CR-Va P4 369 P1 350 RNase MRP RNA RNase P RNA c d S-domain S-domain C-domain P7 P8* C-domain P15 J6/7 J8/9 P7 P6 P9 P15 P8 P4 P12 CR-IV P4 P3 P5 L5 CR-IV P3 P2 P1 P1 P2 P19 P19 RNase MRP RNA RNase P RNA Fig. 1 RNA components of RNase MRP and RNase P. The catalytic (C-) domains of the two related enzymes are similar both in their secondary structures and in their folds, whereas the specificity (S-) domains are distinct. a, b Secondary structure diagrams of the RNase MRP and RNase P RNAs, respectively. c, d Folding of the RNase MRP and RNase P21 RNAs, respectively, color coded as in (a, b). 2 NATURE COMMUNICATIONS | (2020) 11:3474 | https://doi.org/10.1038/s41467-020-17308-z | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17308-z ARTICLE Pop3 Pop3 Snm1 Snm1 180° Pop1 Pop1 Pop4 Pop4 Rpp1B Rmp1 Rpp1B Pop7 Pop7 Pop8 Pop8 Pop6 Rpp1A Pop6 Pop5 Rpp1A Pop3 Snm1 Snm1 180° Pop1 Pop1 Pop4 Pop4 P6 L5L5 P5 P7 P7 LL55 P1P1 Rpp11B Rmp1 Rppp1B P8 J8/9J8/9 PP44 P15P15 P19 P19 P4P4 P2P2 P15P15 Pop7 Pop7 Pop8 Pop8 P3 Pop6 P3 Rpp1A Pop6 Pop5 Rpp1A Fig. 2 Structure of the RNase MRP holoenzyme. Protein components (shown as surfaces) are color coded as marked; the RNA elements (shown as a cartoon) are color coded according to Fig. 1a. from that of RNase P due to the presence of auxiliary RNA illustrative purposes Pop3 was modeled into the RNase MRP elements positioned in the immediate vicinity of the conserved map using its structure in yeast RNase P21. catalytic center, due to the binding of RNase MRP protein Rmp1 Similar to the structures of yeast and human RNases P21,22, near the catalytic center, as well as due to RNA-driven protein RNase MRP structure (Fig. 2) is dominated by proteins. The remodeling. proteins are forming a clamp-like structure embedding RNA and protecting most of it from the solvent, consistent with prior biochemical data30. The basic patches of RNase MRP proteins Results and discussion largely face the RNA component (Supplementary Fig. 4). The Overall structure of RNase MRP. RNase MRP holoenzyme used phylogenetically conserved RNA elements corresponding to the fi in the nal 3D reconstruction was isolated from S. cerevisiae as a catalytic center in RNase P and forming the catalytic center in 1:1 mix with RNase P using a TAP-tag approach with the pur- RNase MRP protrude into the central part of the protein clamp fi 30 “ ” i cation handle fused to protein Pop4 ( Methods ). The isolate opening and are exposed to the solvent. contained all expected proteins and RNA components and RNase Unlike bacterial RNase P RNA31, RNase MRP RNA is missing MRP was active (Supplementary Fig. 1). RNase MRP particles elements that can serve to stabilize its three-dimensional were separated from RNase P during data processing using 3D organization and, similar to eukaryotic RNase P21,22, uses protein fi “ ” classi cation ( Methods ). components as the main structural scaffold (below). The resultant map had an overall resolution of 3.0 Å (Supplementary Table 1), with the central regions as good as 2.5 Å (Supplementary Figs. 2 and 3). The final model included all Structure of RNase MRP RNA. RNase MRP RNA forms an known components of RNase MRP, except for a peripheral essentially single-layered structure dominated by coaxially protein Pop3. The density corresponding to Pop3 was clearly stacked helical regions (Fig. 1c). In the C-domain, helical stem P1 present, but the map quality in this region was not sufficient for a forms a coaxial stack with stem P4, while stems P19, P2, and the reliable atomic reconstruction of the Pop3 structure; for proximal part of P3 form a semi-continuous helix connected to NATURE COMMUNICATIONS | (2020) 11:3474 | https://doi.org/10.1038/s41467-020-17308-z | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17308-z a b G106 α3 L5 P5 U116 C149 Arg107 Pop4 U148U A150 G120 A113 C107 G115G115 A155 (syn/anti) A151 CC114114 A147 P8 C154 Arg233Arg233 A112A112 A14A1141464 A127 α2 U144 A111A111 α19 A128 A110 A129 A130 A131 Pop1Pop1 P4 α7 α6 α1 Smn1 c Snm1 d Pop4 e Pop4 Snm1 α2 Arg46 α2 Lys86 Lys45 α2 Lys38 Arg263 Gln205 Tyr78 U1242 Snm1 A131 A146 α3 U125 A145 Lys75 A130 Pop4 U144 U126 Lys206 Pop4 Fig.
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