Eukaryotic ribosome

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Eukaryotic ribosome. The 40S subunit is on the left, the 60S subunit on the right. The ribosomal RNA (rRNA) core is represented as a grey tube, expansion segments are shown in red. Universally conserved proteins are shown in blue. These proteins have homologs in eukaryotes, archaea and bacteria. Proteins shared only between eukaryotes and archaea are shown in orange, and proteins specific to eukaryotes are shown in red. PDB identifiers 4a17, 4A19, 2XZM aligned to 3U5B, 3U5C, 3U5D, 3U5E 80S 2XZM 4A17 4A19.png
Eukaryotic ribosome. The 40S subunit is on the left, the 60S subunit on the right. The ribosomal RNA (rRNA) core is represented as a grey tube, expansion segments are shown in red. Universally conserved proteins are shown in blue. These proteins have homologs in eukaryotes, archaea and bacteria. Proteins shared only between eukaryotes and archaea are shown in orange, and proteins specific to eukaryotes are shown in red. PDB identifiers 4a17, 4A19, 2XZM aligned to 3U5B, 3U5C, 3U5D, 3U5E

Ribosomes are a large and complex molecular machine that catalyzes the synthesis of proteins, referred to as translation. The ribosome selects aminoacylated transfer RNAs (tRNAs) based on the sequence of a protein-encoding messenger RNA (mRNA) and covalently links the amino acids into a polypeptide chain. Ribosomes from all organisms share a highly conserved catalytic center. However, the ribosomes of eukaryotes (animals, plants, fungi, and large number unicellular organisms all with a nucleus) are much larger than prokaryotic (bacterial and archaeal) ribosomes and subject to more complex regulation and biogenesis pathways. [1] [2] Eukaryotic ribosomes are also known as 80S ribosomes, referring to their sedimentation coefficients in Svedberg units, because they sediment faster than the prokaryotic (70S) ribosomes. Eukaryotic ribosomes have two unequal subunits, designated small subunit (40S) and large subunit (60S) according to their sedimentation coefficients. Both subunits contain dozens of ribosomal proteins arranged on a scaffold composed of ribosomal RNA (rRNA). The small subunit monitors the complementarity between tRNA anticodon and mRNA, while the large subunit catalyzes peptide bond formation.

Contents

Composition

Compared to their prokaryotic homologs, many of the eukaryotic ribosomal proteins are enlarged by insertions or extensions to the conserved core. Furthermore, several additional proteins are found in the small and large subunits of eukaryotic ribosomes, which do not have prokaryotic homologs. The 40S subunit contains a 18S ribosomal RNA (abbreviated 18S rRNA), which is homologous to the prokaryotic 16S rRNA. The 60S subunit contains a 28S rRNA that is homologous to the prokaryotic 23S ribosomal RNA. In addition, it contains a 5.8S rRNA that corresponds to the 5' end of the 23S rRNA, and a short 5S rRNA. Both 18S and 28S have multiple insertions to the core rRNA fold of their prokaryotic counterparts, which are called expansion segments. For a detailed list of proteins, including archaeal and bacterial homologs please refer to the separate articles on the 40S and 60S subunits. Recent research suggests heterogeneity in the ribosomal composition, i.e., that the stoichiometry among core ribosomal proteins in wild-type yeast cells and embryonic stem cells depends both on the growth conditions and on the number of ribosomes bound per mRNA. [3]

Eukaryotic [4] Bacterial [4]
RibosomeSedimentation coefficient80 S70 S
Molecular mass ~3.2×106 Da ~2.0×106 Da
Diameter~250–300 Å ~200 Å
Large subunitSedimentation coefficient60 S50 S
Molecular mass~2.0×106 Da~1.3×106 Da
Proteins4633
rRNAs
  • 25/28 S rRNA (3354 nucleotides)
  • 5 S rRNA (120 nucleotides)
  • 5.8 S rRNA (154 nucleotides)
  • 23S rRNA (2839 nucleotides)
  • 5S rRNA (122 nucleotides)
Small subunitSedimentation coefficient40 S30 S
Molecular mass~1.2×106 Da~0.7×106 Da
Proteins3320
rRNAs
  • 18S rRNA (1753 nucleotides)
  • 16S rRNA (1504 nucleotides)

Structure determination

Initial structures of eukaryotic ribosomes were determined by electron microscopy. First 3D structures were obtained at 30–40 Å resolution for yeast [5] and mammalian ribosomes. [6] [7] Higher resolution structures of the yeast ribosome by cryo-electron microscopy allowed the identification of protein and RNA structural elements. [8] More recently structures at sub-nanometer resolution were obtained for complexes of ribosomes and factors involved in translation. [9] [10] [11] After the determination of the first bacterial [12] [13] [14] and archaeal [15] ribosome structures at atomic resolution in the 1990s, it took another decade until in 2011, high resolution structures of eukaryotic ribosome were obtained by X-ray crystallography, mainly because of the difficulties in obtaining crystals of sufficient quality. [16] [17] [18] The complete structure of a eukaryotic 40S ribosomal structure in Tetrahymena thermophila was published and described, as well as much about the 40S subunit's interaction with eIF1 during translation initiation. [16] The eukaryotic 60S subunit structure was also determined from T. thermophila in complex with eIF6. [17] The complete structure of the eukaryotic 80S ribosome from the yeast Saccharomyces cerevisiae was obtained by crystallography at 3.0 A resolution. [18] These structures reveal the precise architecture of eukaryote-specific elements, their interaction with the universally conserved core, and all eukaryote-specific bridges between the two ribosomal subunits.

Atomic coordinates (PDB files) and structure factors of the eukaryotic ribosome have been deposited in the Protein Data Bank (PDB) under the following accession codes:

ComplexSource OrganismResolutionPDB Identifier [19]
80S:Stm1S. cerevisiae3.0 Å
40S:eIF1T. thermophila3.9 Å
60S:eIF6T. thermophila3.5 Å

Architecture

General features

Some general architectural features of the ribosome are conserved across kingdoms: [20] The structure of the small subunit can be sub-divided into two large segments, the head and the body. Characteristic features of the body include the left and right feet, the shoulder and the platform. The head features a pointed protrusion reminiscent of a bird's beak. In the characteristic "crown view" of the large subunit, structural landmarks include the central protuberance, the L1-stalk and the P-stalk. [21] [22] The majority of the eukaryote-specific RNA and protein elements are found on the solvent-exposed sides of the 40S [16] and 60S [17] subunits. The subunit interface, as well as important functional regions such as the peptidyl transferase center and the decoding site are mostly conserved, with some differences observed in the surrounding regions. In stark contrast to prokaryotic ribosomal proteins, which interact primarily with RNA, the eukaryote-specific protein segments engage in a multitude of protein-protein interactions. Long-distance interactions are mediated by eukaryote-specific helical extensions of ribosomal proteins, and several eukaryotic ribosomal proteins jointly to form inter-protein beta-sheets.

The ribosomal RNA core is represented as a grey tube, expansion segments are shown in red. Universally conserved proteins are shown in blue. These proteins have homologs in eukaryotes, archaea and bacteria. Proteins Shared only between eukaryotes and archaea are shown in orange, and proteins specific to eukaryotes are shown in red.

Co-evolution of rRNA and proteins

The structure of the 40S subunit revealed that the eukaryote-specific proteins (rpS7, rpS10, rpS12 and RACK1), as well as numerous eukaryote-specific extensions of proteins, are located on the solvent-exposed side of the small subunit. [16] Here, they participate in the stabilization of rRNA expansion segments. Moreover, the beak of the 40S subunit is remodeled, as rRNA has been replaced by proteins rpS10 and rpS12. [16] As observed for the 40S subunit, all eukaryote-specific proteins of the 60S subunit (RPL6, RPL22, RPL27, RPL28, RPL29 and RPL36) and many extensions are located at the solvent-exposed side, forming an intricate network of interactions with eukaryotic-specific RNA expansion segments. RPL6, RPL27 and RPL29 mediate contacts between the ES sets ES7–ES39, ES31–ES20–ES26 and ES9–ES12, respectively and RPL28 stabilized expansion segment ES7A. [17]

Ubiquitin fusion proteins

In eukaryotes, the small subunit protein RPS27A (or eS31) and the large subunit protein RPL40 (or eL40) are processed polypeptides, which are translated as fusion proteins carrying N-terminal ubiquitin domains. Both proteins are located next to important functional centers of the ribosome: the uncleaved ubiquitin domains of eS31) and eL40 would be positioned in the decoding site and near the translation factor binding site, respectively. These positions suggest that proteolytic cleavage is an essential step in the production of functional ribosomes. [16] [17] Indeed, mutations of the linker between the core of eS31 and the ubiquitin domain are lethal in yeast. [23]

Active site

Comparisons between bacterial, archaeal and eukaryotic ribosome structures reveal a very high degree of conservation in the active site—aka the peptidyl transferase center (PTC) -- region. None of the eukaryote-specific protein elements is close enough to directly participate in catalysis. [17] However, RPL29 projects to within 18Å of the active site in T. thermophila, and eukaryote-specific extensions interlink several proteins in the vicinity of the PTC of the 60S subunit, [17] [21] while the corresponding 50S proteins are singular entities. [15]

Intersubunit bridges

Contacts across the two ribosomal subunits are known as intersubunit bridges. In the eukaryotic ribosome, additional contacts are made by 60S expansion segments and proteins. [24] Specifically, the C-terminal extension of the 60S protein RPL19 interacts with ES6E of the 40S rRNA, and the C-terminal extension of the 60S protein RPL24 interacts with 40S rpS6 and rRNA helix h10. Moreover, the 60S expansion segments ES31 and ES41 interact with rpS3A(S1) and rpS8 of the 40S subunit, respectively, and the basic 25-amino-acid peptide RPL41 is positioned at the subunit interface in the 80S ribosome, interacting with rRNA elements of both subunits. [21] [24]

Ribosomal proteins with roles in signaling

Two 40S ribosomal proteins (RACK1 and RPS6 (or eS6)) have been implicated in cellular signaling: RACK1, first described as the receptor of activated protein kinase C (PKC), is an integral component of the eukaryotic ribosome and is located at the back of the head. [16] It may link signal-transduction pathways directly to the ribosome though it also has a role in multiple translational processes that appear unrelated (reviewed in [25] ). Ribosomal protein eS6 is located at the right foot of the 40S subunit [16] and is phosphorylated in response to mammalian target of rapamycin (mTOR) signaling. [26]

Functional aspects

Translation initiation

Protein synthesis is primarily regulated at the stage of translation initiation. In eukaryotes, the canonical initiation pathway requires at least 12 protein initiation factors, some of which are themselves large complexes. [27] The structures of the 40S:eIF1 [16] and 60S:eIF6 [17] complexes provide first detailed insights into the atomic interactions between the eukaryotic ribosome and regulatory factors. eIF1 is involved in start codon selection, and eIF6 sterically precludes the joining of subunits. However, structural information on the eukaryotic initiation factors and their interactions with the ribosome is limited and largely derived from homology models or low-resolution analyses. [28] Elucidation of the interactions between the eukaryotic ribosome and initiation factors at an atomic level is essential for a mechanistic understanding of the regulatory processes, but represents a significant technical challenge, because of the inherent dynamics and flexibility of the initiation complexes. The first structure of the mammalian pre initiation complex was done by cryo-electron microscopy. [29] Other structures of initiation complexes followed soon, driven by cryo-EM technical improvements. [30] [31] Those structures will help better understand the process of translation initiation in eukaryotes.

Regulatory roles of ribosomal proteins

Recent genetic evidence has been interpreted to suggest that individual proteins of the eukaryotic ribosome directly contribute to the regulation of translation. [32] [33] [34] However, this interpretation is controversial and some researchers have proposed that genetic changes to ribosomal protein genes indirectly affect overall ribosome numbers or ribosome biogenesis processes. [35] [36]

Protein translocation and targeting

To exert their functions in the cell newly synthesized proteins must be targeted to the appropriate location in the cell, which is achieved by protein targeting and translocation systems. [37] The growing polypeptide leaves the ribosome through a narrow tunnel in the large subunit. The region around the exit tunnel of the 60S subunit is very similar to the bacterial and archaeal 50S subunits. Additional elements are restricted to the second tier of proteins around the tunnel exit, possibly by conserved interactions with components of the translocation machinery. [17] The targeting and translocation machinery is much more complex in eukaryotes. [38]

Ribosomal diseases and cancer

Ribosomopathies are congenital human disorders resulting from defects in ribosomal protein or rRNA genes, or other genes whose products are implicated in ribosome biogenesis. [39] Examples include X-linked Dyskeratosis congenita (X-DC), [40] Diamond–Blackfan anemia, [41] Treacher Collins syndrome (TCS) [41] [42] and Shwachman–Bodian–Diamond syndrome (SBDS). [39] SBDS is caused by mutations in the SBDS protein that affects its ability to couple GTP hydrolysis by the GTPase EFL1 to the release of eIF6 from the 60S subunit. [43]

Therapeutic opportunities

The ribosome is a prominent drug target for antibacterials, which interfere with translation at different stages of the elongation cycle [44] Most clinically relevant translation compounds are inhibitors of bacterial translation, but inhibitors of eukaryotic translation may also hold therapeutic potential for application in cancer or antifungal chemotherapy. [45] Elongation inhibitors show antitumor activity 'in vivo' and 'in vitro'. [46] [47] [48] One toxic inhibitor of eukaryotic translation elongation is the glutarimide antibiotic cycloheximide (CHX), which has been co-crystallized with the eukaryotic 60S subunit [17] and binds in the ribosomal E site. The structural characterization of the eukaryotic ribosome [16] [17] [24] may enable the use of structure-based methods for the design of novel antibacterials, wherein differences between the eukaryotic and bacterial ribosomes can be exploited to improve the selectivity of drugs and therefore reduce adverse effects.

Formation mechanism

Eukaryote ribosomes are produced and assembled in the nucleolus. Ribosomal proteins enter the nucleolus and combine with the four rRNA strands to create the two ribosomal subunits (one small and one large) that will make up the completed ribosome. The ribosome units leave the nucleus through the nuclear pores and unite once in the cytoplasm for the purpose of protein synthesis.

Related Research Articles

<span class="mw-page-title-main">Ribosome</span> Intracellular organelle consisting of RNA and protein functioning to synthesize proteins

Ribosomes are macromolecular machines, found within all cells, that perform biological protein synthesis. Ribosomal RNA is found in the ribosomal nucleus where this synthesis happens. Ribosomes link amino acids together in the order specified by the codons of messenger RNA molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

<span class="mw-page-title-main">Translation (biology)</span> Cellular process of protein synthesis

In biology, translation is the process in living cells in which proteins are produced using RNA molecules as templates. The generated protein is a sequence of amino acids. This sequence is determined by the sequence of nucleotides in the RNA. The nucleotides are considered three at a time. Each such triple results in addition of one specific amino acid to the protein being generated. The matching from nucleotide triple to amino acid is called the genetic code. The translation is performed by a large complex of functional RNA and proteins called ribosomes. The entire process is called gene expression.

<span class="mw-page-title-main">Ribosomal RNA</span> RNA component of the ribosome, essential for protein synthesis in all living organisms

Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal DNA (rDNA) and then bound to ribosomal proteins to form small and large ribosome subunits. rRNA is the physical and mechanical factor of the ribosome that forces transfer RNA (tRNA) and messenger RNA (mRNA) to process and translate the latter into proteins. Ribosomal RNA is the predominant form of RNA found in most cells; it makes up about 80% of cellular RNA despite never being translated into proteins itself. Ribosomes are composed of approximately 60% rRNA and 40% ribosomal proteins by mass.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

<span class="mw-page-title-main">Ribosome biogenesis</span> Cellular process

Ribosome biogenesis is the process of making ribosomes. In prokaryotes, this process takes place in the cytoplasm with the transcription of many ribosome gene operons. In eukaryotes, it takes place both in the cytoplasm and in the nucleolus. It involves the coordinated function of over 200 proteins in the synthesis and processing of the three prokaryotic or four eukaryotic rRNAs, as well as assembly of those rRNAs with the ribosomal proteins. Most of the ribosomal proteins fall into various energy-consuming enzyme families including ATP-dependent RNA helicases, AAA-ATPases, GTPases, and kinases. About 60% of a cell's energy is spent on ribosome production and maintenance.

<span class="mw-page-title-main">Ribosomal protein</span> Proteins found in ribosomes

A ribosomal protein is any of the proteins that, in conjunction with rRNA, make up the ribosomal subunits involved in the cellular process of translation. E. coli, other bacteria and Archaea have a 30S small subunit and a 50S large subunit, whereas humans and yeasts have a 40S small subunit and a 60S large subunit. Equivalent subunits are frequently numbered differently between bacteria, Archaea, yeasts and humans.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

<span class="mw-page-title-main">Prokaryotic large ribosomal subunit</span>

50S is the larger subunit of the 70S ribosome of prokaryotes, i.e. bacteria and archaea. It is the site of inhibition for antibiotics such as macrolides, chloramphenicol, clindamycin, and the pleuromutilins. It includes the 5S ribosomal RNA and 23S ribosomal RNA.

<span class="mw-page-title-main">Prokaryotic small ribosomal subunit</span> Smaller subunit of the 70S ribosome found in prokaryote cells

The prokaryotic small ribosomal subunit, or 30S subunit, is the smaller subunit of the 70S ribosome found in prokaryotes. It is a complex of the 16S ribosomal RNA (rRNA) and 19 proteins. This complex is implicated in the binding of transfer RNA to messenger RNA (mRNA). The small subunit is responsible for the binding and the reading of the mRNA during translation. The small subunit, both the rRNA and its proteins, complexes with the large 50S subunit to form the 70S prokaryotic ribosome in prokaryotic cells. This 70S ribosome is then used to translate mRNA into proteins.

Ribosomal particles are denoted according to their sedimentation coefficients in Svedberg units. The 60S subunit is the large subunit of eukaryotic 80S ribosomes, with the other major component being the eukaryotic small ribosomal subunit (40S). It is structurally and functionally related to the 50S subunit of 70S prokaryotic ribosomes. However, the 60S subunit is much larger than the prokaryotic 50S subunit and contains many additional protein segments, as well as ribosomal RNA expansion segments.

<span class="mw-page-title-main">40S ribosomal protein S5</span> Protein-coding gene in the species Homo sapiens

40S ribosomal protein S5 is a ribosomal subunit of the Eukaryotic ribosome (80S) complex. In humans it is encoded by the RPS5 gene.

<span class="mw-page-title-main">EIF1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. It is related to yeast SUI1.

The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal particles are denoted according to their sedimentation coefficients in Svedberg units. It is structurally and functionally related to the 30S subunit of 70S prokaryotic ribosomes. However, the 40S subunit is much larger than the prokaryotic 30S subunit and contains many additional protein segments, as well as rRNA expansion segments.

<span class="mw-page-title-main">Protein synthesis inhibitor</span> Inhibitors of translation

A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.

Translational regulation refers to the control of the levels of protein synthesized from its mRNA. This regulation is vastly important to the cellular response to stressors, growth cues, and differentiation. In comparison to transcriptional regulation, it results in much more immediate cellular adjustment through direct regulation of protein concentration. The corresponding mechanisms are primarily targeted on the control of ribosome recruitment on the initiation codon, but can also involve modulation of peptide elongation, termination of protein synthesis, or ribosome biogenesis. While these general concepts are widely conserved, some of the finer details in this sort of regulation have been proven to differ between prokaryotic and eukaryotic organisms.

<span class="mw-page-title-main">Eukaryotic initiation factor 3</span> Multiprotein complex that functions during the initiation phase of eukaryotic translation

Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 consists of 13 nonidentical subunits (eIF3a-m) with a combined molecular weight of ~800 kDa, making it the largest translation initiation factor. The eIF3 complex is broadly conserved across eukaryotes, but the conservation of individual subunits varies across organisms. For instance, while most mammalian eIF3 complexes are composed of 13 subunits, budding yeast's eIF3 has only six subunits.

<span class="mw-page-title-main">Eukaryotic initiation factor 4F</span> Multiprotein complex used in gene expression

Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.

The 43S preinitiation complex is a ribonucleoprotein complex that exists during an early step of eukaryotic translation initiation. The 43S PIC contains the small ribosomal subunit (40S) bound by the initiation factors eIF1, eIF1A, eIF3, and the eIF2-Met-tRNAiMet-GTP ternary complex (eIF2-TC).

Archaeal initiation factors are proteins that are used during the translation step of protein synthesis in archaea. The principal functions these proteins perform include ribosome RNA/mRNA recognition, delivery of the initiator Met-tRNAiMet, methionine bound tRNAi, to the 40s ribosome, and proofreading of the initiation complex.

References

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  2. ↑ "80S Ribosomes, Eukaryotic Ribosomes, Prokaryotic Ribosomes, Nucleic Acids, Sedimentation Coefficient". www.microbiologyprocedure.com. Archived from the original on 2009-06-23. Retrieved 2009-08-06.
  3. ↑ Slavov, Nikolai; Semrau, Stefan; Airoldi, Edoardo; Budnik, Bogdan; van Oudenaarden, Alexander (2015). "Differential Stoichiometry among Core Ribosomal Proteins". Cell Reports. 13 (5): 865–873. doi:10.1016/j.celrep.2015.09.056. ISSN   2211-1247. PMC   4644233 . PMID   26565899.
  4. 1 2 Values are based on the ribosomes of Tetrahymena thermophila (PDB: 4V8P) and Thermus thermophilus (PDB: 4V5D). The exact size, weight and number of proteins varies from organism to organism.
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