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. 2010 Sep 1;7(5):534–539. doi: 10.4161/rna.7.5.12302

The P3 domain of eukaryotic RNases P/MRP

Making a protein-rich RNA-based enzyme

Anna Perederina 1, Andrey S Krasilnikov 1,✉
PMCID: PMC3073249  PMID: 20523128

Abstract

Nuclear Ribonuclease (RNase) P is a universal essential RNA-based enzyme made of a catalytic RNA component and a protein part; eukaryotic RNase P is closely related to a universal eukaryotic ribonucleoprotein RNase MRP. The protein part of the eukaryotic RNases P/MRP is dramatically more complex than that in bacterial and archaeal RNases P. The increase in the complexity of the protein part in eukaryotic RNases P/MRP was accompanied by the appearance of a novel structural element in the RNA component: an essential and phylogenetically conserved helix-loop-helix P3 RNA domain. The crystal structure of the P3 RNA domain in a complex with protein components Pop6 and Pop7 has been recently solved. Here we discuss the most salient structural features of the P3 domain as well as its possible role in the evolutionary transition to the protein-rich eukaryotic RNases P/MRP.

Key words: ribonuclease P, RNase P, ribonuclease MRP, RNase MRP, ribonucleoprotein, ribozyme, P3 domain, Pop6, Pop7, RNA-protein interactions

Introduction

Nuclear Ribonuclease (RNase) P1 and RNase MRP2 are closely related site-specific endoribonucleases. RNase P is a universal essential enzyme found in all three domains of life.3 RNase P is responsible for the maturation of the 5′-end of tRNA and has other functions in the cell, including a recently suggested involvement in transcription.4,5 RNase MRP is an essential ribonuclease found exclusively in eukaryotes.6 Nuclear RNase MRP is involved in the maturation of rRNA7,8 and in the regulation of the cell cycle.9,10 A small fraction of RNase MRP is also found in the mitochondria,11 although the composition and activity of the mitochondrial enzyme is distinct.12

Nuclear RNase P and RNase MRP are catalytic ribonucleoproteins. The RNA component of RNase P is the enzyme's catalytic moiety throughout the three domains of life.13–16 The RNA components of the RNases P have similar secondary structures (Fig. 1A–D) with several phylogenetically conserved elements that constitute the core of these enzymes;17 peripheral elements in RNase P RNAs from different domains of life may vary considerably. The RNA component of RNase P can be divided into two structural domains: the specificity (S-) domain that is responsible for the recognition of the TΨC stem-loop of the substrate pretRNA, and the catalytic (C-) domain that contains the active site (Fig. 1A–D).18,19 The RNA component of RNase MRP contains a part (Domain 1, Fig. 1E) closely resembling the catalytic domain of RNase P, and a distinct part (Domain 2, Fig. 1E) replacing the specificity domain. The similarity between the catalytic domain of RNase P and the corresponding Domain 1 in RNase MRP strongly suggests that the two enzymes share a common mechanism of catalysis, while the divergence of the specificity domain in RNase P and Domain 2 in RNase MRP is consistent with the diverse specificities of RNases P and MRP.

Figure 1.

Figure 1

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Schematic diagrams of the RNA components of RNases P/MRP. (A) The RNA component of bacterial RNase P (an A-type RNA component is shown). (B) The RNA component of archaeal RNase P (an M-type RNA component is shown). (C) The RNA component of S. cerevisiae RNase P. (D) The RNA component of human RNase P. (E) The RNA component of S. cerevisiae RNase MRP. Secondary structure diagrams and the nomenclature of structural elements are shown according to refs. 36,37,46–50. The specificity (S-) and catalytic (C-) domains of RNases P and corresponding domains (1 and 2) of RNase MRP are separated by dotted lines. Tertiary interactions are shown as thin lines.

The size and composition of the protein parts of RNases P from different domains of life vary dramatically. Bacterial RNase P has a single small protein that is less than 1/10th of the RNA component by mass. Archaeal RNase P has four or five proteins (aPop4, aPop5, aRpp1, aRpr2 and, likely, aPop3).20,21 Eukaryotic RNase P has a complex protein composition (nine proteins in S. cerevisiae: Pop1, Pop3 (a homologue of archaeal RNase P protein aPop3), Pop4 (a homologue of archaeal aPop4), Pop5 (a homologue of archaeal aPop5), Pop6, Pop7, Pop8, Rpp1 (a homologue of archaeal aRpp1), and Rpr2 (a homologue of archaeal aRpr2));22–26 the protein part of eukaryotic RNase P is significantly larger than its catalytic RNA component. RNase MRP has a protein part that is very similar to that of eukaryotic RNase P: in S. cerevisiae eight of the ten RNase MRP proteins (Pop1, Pop3, Pop4, Pop5, Pop6, Pop7, Pop8 and Rpp1) are shared with RNase P,26 while two proteins (Snm1,27 and Rmp1,28) are unique. All protein components of RNases P/MRP are essential.26,28,29 The reasons for the increased complexity of the RNA components in the more evolutionarily advanced organisms are not clear.

The P3 RNA Domain

The increased complexity of the protein part of eukaryotic RNases P/MRP was accompanied by the appearance of a novel structural feature of the RNA component: a helix-loop-helix domain P3 (Fig. 1C–E). The helix-loop-helix P3 RNA domain replaces a helical stem P3 universally found in bacterial and archaeal RNases P (Fig. 1) and is a characteristic feature of practically all eukaryotic RNases P/MRP.30–32 The P3 RNA domain is an essential structural feature of eukaryotic enzymes and its deletion or truncation (affecting the loop region) is lethal.33,34

The P3 RNA domain is involved in extensive interactions with proteins, the only exception being the distal part of the left (Fig. 1C–E) helical stem.35,36 Sequences of the P3 domains of RNase P and RNase MRP show a clear pattern of co-variation when the enzymes from the same organism are compared.31,32,37 In footprinting assays, the proteins of RNases P and MRP holoenzymes protect practically identical parts of their respective P3 domains.36 Moreover, the P3 domains of yeast RNases P and MRP can be interchangeable,30 which strongly suggests a similarity of the structural organizations and functional roles of the P3 domain in the two enzymes.

In S. cerevisiae, protein components Pop6 and Pop7 are shown to interact with the P3 RNA domain;38 similar results were obtained for the human enzymes.39 In addition, protein component Pop1 is also likely to bind to the P3 RNA domain.31

The Crystal Structure of the P3 RNA Domain in a Complex with Protein Components Pop6 and Pop7

The crystal structure of the P3 RNA domain from S. cerevisiae RNase MRP in a complex with protein components Pop6 and Pop7 has recently been reported.40,41 The structure of the P3 domain of S. cerevisiae RNase P is expected to be very similar to that of RNase MRP,41 as are the P3 domains of human RNases P/MRP.41,42

The P3 RNA domain folds into two helical stems separated by a large internal loop (Fig. 2). Both of the RNA strands forming the internal loop are well structured. Their structures are stabilized mostly by interactions with proteins as well as by the stacking of nucleobases; surprisingly, no base pairing (including noncanonical) is observed in the internal loop of the P3 RNA domain. The distal (left in Figs. 1 and 2) helical stem of the P3 domain interacts with the protein component Pop6, that enters the major groove of this stem (Fig. 2). Several nucleotides of P3 internal loop (mostly its lower strand, Fig. 2) are also involved in interactions with Pop6. In the crystal structure, the P3 domain RNA-Pop6 interaction buries 900 Å of the protein's solvent accessible surface area;41 however, Pop6 does not bind to the P3 domain RNA in the absence of Pop7,38 possibly due to the role of Pop7 in the P3 domain RNA folding. Pop7 is involved in extensive interactions with both strands of the P3 domain internal loop; interactions of Pop7 with P3 domain RNA bury 1,830 Å of the protein's solvent accessible area.41 A phylogenetically conserved ACR triad41 located in the lower strand of the P3 internal loop is sandwiched between the N-terminal region of Pop7 and the rest of this protein, thus ordering the N-terminal part of Pop7.41 For more details on the RNA fold and RNA-protein interactions in the P3 domain see ref. 41.

Figure 2.

Figure 2

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Crystal structure of the P3 RNA domain of S. cerevisiae RNase MRP in a complex with protein components Pop6 and Pop7.41 The RNA component is shown in orange; the terminal loop of the P3 RNA domain (missing in the crystal structure) is shown as a dashed orange line; Pop6 is shown in green; Pop7 is shown in blue; disordered loops in Pop6 and Pop7 are schematically shown as dotted lines.

Protein components Pop6 and Pop7 form a heterodimer.38 The formation of this heterodimer is required for the proper folding of Pop7, which is not soluble unless coexpressed with Pop6.38 While the sequences of Pop6 and Pop7 are very diverse, both proteins adopt similar βαβαβαββ folds (Fig. 3A and B).41 The folds of Pop6 and Pop7 are closely related to the βαβαββ fold of archaeal and eukaryotic nucleic acid binding proteins of the Alba family.43 A bioinformatics analysis of Pop7 and the human homologue of Pop6 (Rpp25) suggests that they originated from the Alba family of proteins,44 in consistence with the observed structural organization of Pop6 and Pop7 (it should be noted that sequences of Pop7 and, especially, Pop6 have only minimal similarity to Alba41).

Figure 3.

Figure 3

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S. cerevisiae protein components Pop6 and Pop7. (A) Pop6. β-stands are shown in red; α-helices are shown in cyan; loops are shown in magenta; disordered loop is schematically shown by a dotted line; N- and C-termini are marked. (B) Pop7. The designations are the same as in (A). (C) Pop6/Pop7 heterodimer superposed on a typical Alba dimer (PDB ID 1H0X). Pop6 is shown in green; Pop7 is shown in cyan; Alba proteins are shown in brown.

Pop6 and Pop7, like most of the RNase P/MRP proteins, are basic (pI 9.3). Their positively charged residues are concentrated in the area that is involved in direct interactions with RNA (Fig. 4A). Remarkably, the basic Pop7 has a patch of acidic residues forming a large loop (Fig. 4A). (This loop was largely disordered in crystals and thus was not included in the structure; the loop in Fig. 4A shows a result of modeling that is based on available Alba structures with similar loops. While the actual orientation of the loop and details of its organization may differ from those modeled, Fig. 4A reflects the strikingly acidic character of the Pop7 loop). The negatively charged loop seems to be well suited for interactions with other (predominantly basic) proteins in RNases P/MRP. The presence of acidic residues in this region of Pop7 appears to be conserved in eukaryotes, although the length of the loop may vary substantially.41

Figure 4.

Figure 4

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The electrostatic potential of the solvent accessible surface of the Pop6/Pop7 heterodimer is similar to that of a typical Alba dimer. Positively charged areas are shown in blue, neutral—in while, negatively charged—in red. (A) Pop6/Pop7 heterodimer. The P3 RNA domain is shown in red. The diagram is based on the crystal structure of the complex,41 but models of the disordered loops of Pop6 (shown by green dashed line) and Pop7 (blue dashed line) are added. While the actual structural features of the modeled loops may differ from those shown, the diagram reflects overall charges of the disordered loops as defined by their amino acid sequences. (B) A typical Alba dimer (PDB ID 1H0X) shown together with the P3 RNA domain (in red).41 The Alba dimer is shown in the same orientation as Pop6/Pop7 above. To position the P3 RNA domain, the Pop6/Pop7 heterodimer from the Pop6/Pop7-P3 RNA complex41 has been superposed on the Alba dimer (as in Fig. 3C) and the resultant position of RNA is shown.

A Role for the P3 Domain in Eukaryotic RNases P/MRP

The appearance of the conserved helix-loop-helix P3 RNA domain clearly parallels a jump in the complexity of the protein part in the eukaryotic RNase P and RNase MRP compared to the bacterial and archaeal enzymes. It is not clear why eukaryotic enzymes of the RNase P/MRP family acquired their complex protein part. In addition to the roles equivalent to those played by the single protein in bacterial RNase P, one of the likely functions of the proteins in archaeal and eukaryotic RNases P is to compensate for the disappearance of RNA elements that stabilize the tertiary structure of bacterial RNases P but are missing in the archaeal and eukaryotic enzymes.

It should be noted, however, that eukaryotic RNase P RNAs (Fig. 1C and D) are similar in their relative simplicity to some archaeal RNases P (the archaeal M-type, Fig. 1B), and that the latter are capable of compensating for the loss of tertiary RNA-RNA interactions with just four or five proteins (which are homologous to eukaryotic RNase P/MRP proteins: aPop4, aPop5, aRpp1, aRpr2, and, likely, aPop3). Thus it seems likely that the primary functions of the additional four proteins appearing in the eukaryotic RNase P (Pop1, Pop6, Pop7 and Pop8) are not a substitution for the single bacterial protein and the stabilization of the RNA fold. The additional proteins might have been acquired in response to the increased complexity of the intracellular environment that required the fine-tuning of the specificity of the enzyme, interactions with other parts of the cellular machinery (including controllable localization), or the acquisition of novel functions/specificities.45

In any scenario, the acquisition of the four additional proteins by eukaryotic RNase P more than doubled (compared to archaeal RNase P) the size of the protein part. The role of the helix-loop-helix P3 RNA domain, the only phylogenetically conserved structural element that is unique to eukaryotic enzymes, is likely to provide the necessary link between the novel eukaryotic proteins and the RNA moiety. Identities of the proteins that bind to the P3 RNA domain (Pop1, Pop6 and Pop7) confirm this suggestion. While the details of the interaction of Pop1 with the P3 RNA domain are yet to be determined, available information on the Pop6/Pop7 heterodimer and its likely localization in the holoenzyme41 is consistent with the role of the P3 RNA domain as a protein-binding hub that evolved to accommodate (and make possible) the growing protein part in the eukaryotic enzymes.

Alba proteins have a propensity to dimerize, and several structures of such dimers are available. The juxtaposition of Pop6 and Pop7 in their heterodimer is remarkably similar to the juxtaposition of the proteins in a typical Alba dimer, and thus in the course of evolution the overall structural organization of the Pop6/Pop7 heterodimer did not substantially diverge from that of a typical Alba dimer (Fig. 3C). Moreover, a comparison of the surface electrostatic potential distribution of a typical Alba dimer (Fig. 4B) with that of the Pop6/Pop7 heterodimer (Fig. 4A) shows that the overall localization of the positively charged area is conserved. This suggests that the evolutionary predecessor of the Pop6/Pop7 heterodimer in early eukaryotic RNase P, likely an Alba-family dimer, interacted with the RNA component using generally the same interface as the modern Pop/Pop7 (Fig. 4B).

It is tantalizing to suggest an evolutionary path for eukaryotic RNase P/MRP where the P3 RNA domain was first present as a simple helical stem P3 (as it still exists in the bacterial and archaeal enzymes), and then an Alba-family dimer was recruited to bind this stem (not necessarily in a highly specific manner). The binding of this Alba-family dimer was followed by a co-evolution of the P3 stem (which has developed its internal loop allowing for more specific binding) and the Alba dimer (where the two Alba proteins diverged to interact with other protein components of the complex and, possibly, recruit additional protein components such as Pop1 through interactions with novel features such as the acidic variable loop in Pop7).

Conclusions

The available structural results are consistent with the hypothesis that the P3 RNA domain plays the role of the protein-binding hub that has evolved from the P3 stem found in bacterial and archaeal RNases P to accommodate the growing protein part of eukaryotic enzymes of the RNase P/MRP family. It is likely that the P3 RNA domain serves to make possible the addition of protein components that do not have homologues in archaeal RNase P, namely Pop1, Pop6 and Pop7. The reasons for the addition of these proteins are not known, but it is likely that their presence reflects additional requirements that are unique to the cellular environment of eukaryotic cells. While emerging structural information provides clues related to the structural organization of eukaryotic RNases P/MRP, the structural and functional roles of proteins need further clarification.

Acknowledgements

We thank Lydia Krasilnikova for her help with the manuscript preparation. This work was supported by NIH grant GM085149 to A.S.K.

Abbreviations

RNase

ribonuclease

tRNA

transfer RNA

rRNA

ribosomal RNA

S. cerevisiae

Saccharomyces cerevisiae

S-domain

specificity domain

C-domain

catalytic domain

Footnotes

References

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