Structure of the Base of the L7/L12 Stalk of the Haloarcula marismortui Large Ribosomal Subunit: Analysis of L11 Movements

doi:10.1016/j.jmb.2007.05.091

Journal of Molecular Biology

Volume 371, Issue 4, 24 August 2007, Pages 1047-1059

https://doi.org/10.1016/j.jmb.2007.05.091 Get rights and content

Abstract

Initiation factors, elongation factors, and release factors all interact with the L7/L12 stalk of the large ribosomal subunit during their respective GTP-dependent cycles on the ribosome. Electron density corresponding to the stalk is not present in previous crystal structures of either 50 S subunits or 70 S ribosomes. We have now discovered conditions that result in a more ordered factor-binding center in the Haloarcula marismortui (H.ma) large ribosomal subunit crystals and consequently allows the visualization of the full-length L11, the N-terminal domain (NTD) of L10 and helices 43 and 44 of 23 S rRNA. The resulting model is currently the most complete reported structure of a L7/L12 stalk in the context of a ribosome. This region contains a series of intermolecular interfaces that are smaller than those typically seen in other ribonucleoprotein interactions within the 50 S subunit. Comparisons of the L11 NTD position between the current structure, which is has an NTD splayed out with respect to previous structures, and other structures of ribosomes in different functional states demonstrates a dynamic range of L11 NTD movements. We propose that the L11 NTD moves through three different relative positions during the translational cycle: apo-ribosome, factor-bound pre-GTP hydrolysis and post-GTP hydrolysis. These positions outline a pathway for L11 NTD movements that are dependent on the specific nucleotide state of the bound ligand. These three states are represented by the orientations of the L11 NTD relative to the ribosome and suggest that L11 may play a more specialized role in the factor binding cycle than previously appreciated.

Introduction

While the high resolution crystal structure of the 50 S subunit highlighted the central role of RNA in ribosome function, it also revealed two protein-rich regions on the large ribosomal subunit, the outside of the exit tunnel and the L7/L12 stalk, both of which are responsible for mediating interactions with numerous cellular factors.¹ The first protein-rich region, the L7/L12 stalk, is a large, highly mobile lateral protuberance on the 50 S ribosomal subunit. The L7/L12 stalk mediates interactions with ribosomal factors associated with protein synthesis. This role as a ubiquitous binding site has led the L7/L12 stalk to be referred to as either the factor-binding region or as the GTPase associated center if referred to in conjunction with the sarcin-ricin loop (SRL). The second protein-rich region of the large ribosomal subunit is comprised of seven proteins that form a ring around the end of the exit-tunnel. These proteins are responsible for mediating interactions with components involved in co-translational folding, such as trigger factor, or components of co-translational targeting and secretion such as the signal recognition particle (SRP) and the translocon.

The L7/L12 stalk, hereafter referred to as the stalk, is composed of ribosomal proteins (r-proteins) L10, L11, and L7/L12, as well as a segment of domain II of 23 S RNA. RNA helices 43 and 44 (H43/44) form a platform on which L10 and L11 simultaneously bind. These three components form the base of the stalk. Depending on the species, two or three copies of the L7/L12 dimer (the same protein except for a post-translational N-terminal acetylation) bind specifically to the C-terminal tail of L10.²

The stalk forms the bulk of the binding site for the ribosomal factors that are involved in each stage of translation. Initiation, elongation, translocation and release are all mediated through the nucleotide hydrolysis by a translation factor GTPase. Initiation Factor-2 (IF2) promotes assembly of the small and large ribosomal subunits by the recruitment of the initiator tRNA. Aminoacylated tRNAs are delivered to the A site by Elongation Factor Tu (EF-Tu). After peptide-bond formation, the translocation of the tRNAs from the A site and P site to the P site and E site, respectively, is driven by Elongation Factor G (EF-G). After hydrolysis of the ester-linked polypeptide from the tRNA by Release Factor 1 and 2 (RF1 and RF2), the factors are released from the ribosome by another GTPase, Release Factor 3 (RF3). The GTPase activities of many of the translational factors are affected, either stimulated or inhibited, by the thiazole class of antibiotics. These antibiotics, for example thiostrepton, bind to the stalk and presumably lock the stalk components in a fixed conformation.³ The GTPases that catalyze nearly every step of translation all perform their respective functions while bound to the stalk.

The mobile nature of the stalk in the absence of bound factor has made obtaining its high-resolution structure elusive. While the stalk proteins constitute roughly 20% of the total protein mass of the large ribosomal subunit, this region has lacked clear and interpretable electron density for both L10 and L7/L12 in the recent high-resolution X-ray structures of the 50 S ribosomal subunit and 70 S ribosome.1., 4., 5., 6. The two most recent high-resolution structures of the 70 S ribosome complexed with tRNA have even less structural information on this region as they both lack models for all of the stalk proteins, L7/L12, L10, and L11.7., 8. While no high resolution structure exists that describes the assembly of stalk in the context of the ribosome, a model of the 50 S subunit with its stalk has been constructed using the separate crystal structure of the L10 complex with L7/L12.²

Cryo-EM maps have been more successful in illuminating the overall stalk structure. The low resolution structure of the 70 S ribosome complex with EF-G determined by cryo-EM demonstrated that the N-terminal domain (NTD) of L11 adopts different orientations upon binding EF-G complexed with different nucleotides⁹ and that factor binding also causes a rearrangement in the C-terminal domain (CTD) of L12.¹⁰ Complexes of the 70 S ribosomes with EF-Tu also show that the position of L11 varies upon factor binding.¹¹ Mitra et al.¹² discuss the movements of H43/44 in various cryo-EM structures, however coordinates of the RNA have not been deposited, which precludes our discussion of these movements. Several molecular dynamics simulations also support the hypothesis that this RNA platform is highly mobile.13., 14. The conclusion that the stalk undergoes structural rearrangements upon factor binding is not a new concept. Protease digestion experiments on ribosomes complexed with either EF-Tu or EF-G revealed a different digestion pattern for L12 depending on not only if a factor was bound, but also on the specific nucleotide state of the factor.15., 16. These results highlight the mobile nature of the stalk and imply that its dynamics are linked to the translation cycle.

We present an X-ray crystal structure of the Haloarcula marismortui (H.ma) large ribosomal subunit that contains the most complete atomic model of the stalk to date. Our structure allows us to visualize the components of the stalk base that include residues 7–132 of L10, approximately the first third of the protein that forms the NTD, and residues 3–70 of the NTD of L11 in addition to the previously identified L11 CTD (71–129) and H43/44 (1142–1222).¹⁷ Analysis of the position of the L11 NTD in the structure presented here as well as its position in other L11 structures has led us to present a new model and nomenclature that describes the path through which the L11 NTD moves during factor binding.

While our initial aim was to investigate the interactions between the ribosome and the nascent polypeptide-associated complex (NAC), its addition to our 50 S subunit crystals stabilized the stalk and improved our view of it. NAC was first identified as a protein that could be cross-linked to ribosome nascent-chain complexes (RNCs),¹⁸ and these cross-links could occur with nascent chains as short as 30 amino-acid residues long. Cross-linking experiments between NAC and ribosomes resulted in chemical cross-links to r-protein L23.¹⁹ NAC also has been shown to interact with eukaryotic r-protein L25 (archaeal L23) in a yeast two-hybrid assay.²⁰ These results suggest that NAC interacts with the ribosome at the end of the exit-tunnel, near the binding site of both SRP and the translocon. Since the identification of NAC in 1994, there has been no consensus on what its function is. Among others, possible roles that have been attributed to NAC include (1) a component that enhances the accuracy of SRP by sequestering inappropriate RNCs away from SRP,¹⁸ (2) a negative regulator of SRP function that works by inhibiting the interactions between SRP and empty ribosomes or RNCs without a signal sequence,²¹ or (3) an enhancer of targeting accuracy that functions by inhibiting the intrinsic interaction between the translocon and the ribosome,22., 23. although several laboratories have contested any role for NAC in the membrane association of ribosomes.24., 25.

Due to the obvious interest in the structural basis of NAC function, we attempted to prepare a complex between NAC and the H.ma 50 S subunit by soaking NAC into existing ribosome crystals. While this approach to obtain a crystal structure of the complex between the ribosome and NAC failed to show any evidence of a NAC binding site, we discovered that solutions containing NAC stabilized the 50 S subunit and resulted in a more ordered L7/L12 stalk, whose structure we present here.

Section snippets

Results

In pursuit of our initial goal to obtain the structure of a complex between H.ma 50 S subunit and H.ma NAC, crystals of the large ribosomal subunit were soaked in a solution containing the purified protein. Data collected from crystals soaked in buffer containing NAC diffracted to 3 Å resolution and maintained both the same space group and unit cell dimensions as the apo crystals (Table 1). Electron density maps did not contain any additional electron density in the region at the end of the

Structural conservation of the stalk’s function during translation

The r-proteins of the L7/L12 stalk are homologous in both structure and function across all three kingdoms. The structure of the H.ma L10 structure superimposes on that of the bacterial L10 protein² with a root-mean squared deviation (RMSD) of 3.3 Å over 120 C^α atoms. Comparisons of all of the L11 structures used in the superpositions show that the structure of this protein is more conserved than that of L10; the NTD of L11 superimposes with an RMSD of 1.3 Å over 60 C^α atoms, while the CTDs

Cloning, expression and purification of nascent polypeptide-associated complex (NAC)

The gene corresponding to NAC was cloned from H.ma genomic DNA into pROEX-HTb vector (Invitrogen) between the BamHI and EcoRI cut sites. E.coli cells BL21(DE3)pLysE (Invitrogen) transformed with this vector were grown in LB containing ampicillin and chloramphenicol at 37 °C. Cells were induced at an A_600 nm of 0.4 and harvested 4 h later. Cells were lysed in 100 mM Tris (pH 8), 0.5 M (NH₄)Cl, 1.2 M KCl, 10% (v/v) glycerol. Clarified lysate was loaded onto a Nickel column in Buffer A (50 mM Tris

Acknowledgements

We thank the staff at APS beamline 24-ID and at ALS beamline 8.2.2. We also thank Scott Bailey for critical reading of the manuscript and Gregor Blaha for helpful discussions and data collection, and the staff of the CSB core facility at Yale. This work was supported by NIH grant GM 22778 to T.A.S.

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Journal of Molecular Biology

Structure of the Base of the L7/L12 Stalk of the Haloarcula marismortui Large Ribosomal Subunit: Analysis of L11 Movements

Abstract

Introduction

Section snippets

Results

Structural conservation of the stalk’s function during translation

Cloning, expression and purification of nascent polypeptide-associated complex (NAC)

Acknowledgements

Cell

Cell

Cell

J. Mol. Biol.

Mol. Cell

FEBS Letters

Biochimie

J. Mol. Biol.

J. Biol. Chem.

Curr. Biol.

FEBS Letters

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Cell

J. Biol. Chem.

J. Biol. Chem.

Biochimie

Cell

Cell

The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution

Science

Involvement of specific portions of rRNA in defined ribosomal functions: a study utilizing antiobiotics

Structures of the bacterial ribosome at 3.5 Å resolution

Science

Structural basis for messenger RNA movement on the ribosome

Nature

Structure of the 70S ribosome complexed with mRNA and tRNA

Science