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• W2045939425 abstract "Ban and coworkers at ETH are step-by-step widening the perspective of the actions on the ribosome (Bingel-Erlenmeyer et al., 2008Bingel-Erlenmeyer R. Kohler R. Kramer G. Sandikci A. Antolic S. Maier T. Schaffitzel C. Wiedmann B. Bukau B. Ban N. A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing.Nature. 2008https://doi.org/10.1038/nature06683Crossref Scopus (78) Google Scholar). The last one in the series is the localization of the binding site of peptide deformylase at the mouth of the polypeptide exit tunnel. Ban and coworkers at ETH are step-by-step widening the perspective of the actions on the ribosome (Bingel-Erlenmeyer et al., 2008Bingel-Erlenmeyer R. Kohler R. Kramer G. Sandikci A. Antolic S. Maier T. Schaffitzel C. Wiedmann B. Bukau B. Ban N. A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing.Nature. 2008https://doi.org/10.1038/nature06683Crossref Scopus (78) Google Scholar). The last one in the series is the localization of the binding site of peptide deformylase at the mouth of the polypeptide exit tunnel. Protein synthesis, translation of mRNA into protein, is performed by ribosomes. In bacteria, translation is initiated by formation of an initiation complex in which a special initiator tRNA charged with formylated methionine (fMet) binds to the mRNA start codon. The formyl group is a protective group that prevents unwanted side reactions at the N-terminal end of the peptide. Successive amino acids are brought by tRNA molecules, complementary to subsequent mRNA codons, and linked together at the catalytic peptidyl transferase center (PTC). As the polypeptide grows, it travels through a 15 Å wide tunnel through the large ribosomal subunit, emerging, after about 100 Å, on the back side of the ribosome (Ban et al., 2000Ban N. Nissen P. Hansen J. Moore P.B. Steitz T.A. Science. 2000; 289: 905-920Crossref PubMed Scopus (2709) Google Scholar). In addition to parts of the 23S rRNA, ribosomal proteins L4 and L22 surround the tunnel. The tunnel exit itself is surrounded by a protein-rich surface, which includes ribosomal proteins L17, L22, L23, L29, and L32 (Figure 1). As soon as the first few amino acids of a protein have emerged through the exit, the N-terminal formyl group is removed by an enzyme, peptide deformylase (PDF), often followed by the removal of the N-terminal methionine by methionine amino-peptidase (MAP). Cotranslational chaperones, as well as the complexes involved in targeting proteins for insertion into or transport across the membrane, interact with both the nascent chain and this region of the ribosome. In recent years, new structural and functional insights into these processes have been gained through a combination of biochemistry, crystallography, and single particle cryo-EM. The most recent piece of this jigsaw puzzle is contributed by Bingel-Erlenmeyer et al., 2008Bingel-Erlenmeyer R. Kohler R. Kramer G. Sandikci A. Antolic S. Maier T. Schaffitzel C. Wiedmann B. Bukau B. Ban N. A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing.Nature. 2008https://doi.org/10.1038/nature06683Crossref Scopus (78) Google Scholar in a study clarifying how bacterial PDF interacts with the ribosome. Bacterial PDFs are single domain metalloproteases with a size of ∼20 kDa (Figure 1A). They can be divided into two classes based on differences in their C terminus. E. coli PDF belongs to class I, containing a basic C-terminal helix that is dispensable for catalytic activity. Bingel-Erlenmeyer et al. employed pelleting and surface plasmon resonance binding experiments to show that this C-terminal helix constitutes the ribosome-binding module of PDF, interacting with the 50S ribosomal subunit. Interestingly, the isolated helix displayed the same binding affinity as the intact PDF. The authors confirmed the functional importance of this interaction by in vivo experiments where a C-terminal helix deletion reduced the bacterial growth rate 10-fold. Next, Bingel-Erlenmeyer et al. solved a 3.7 Å crystal structure of the C-terminal helix of PDF in complex with the E. coli 70S ribosome. Structural analysis placed the helix in a groove between ribosomal proteins L22 and L32, close to the C terminus of L17. Using the crystal structure of E. coli PDF, the direction and register of the helix could be identified albeit at moderate resolution, which is somewhat risky, since side chains are not always visible in the density. In this case, however, the combination of a proline-mediated kink in the N-terminal end of the helix and some well-ordered large side chains were used for placing the helix. Furthermore, the entire PDF was placed according to the fragment structure. In this procedure it is assumed that the fragment (the C-terminal helix) will not move significantly with respect to the rest of the enzyme when bound to the ribosome. In the available structures of class I PDFs, the C-terminal helix has a fixed position relative to the catalytic domain. Thus, it can serve as anchor point, allowing the entire PDF structure to be placed with reasonable accuracy producing a model of ribosome/PDF complex. In this model, the entrance of the PDF active site is oriented toward the ribosome exit tunnel, at a distance spanned by 13 amino acids in extended polypeptide conformation. The best characterized cotranslational chaperone is the bacterial trigger factor (TF), a 48 kDa protein forming one head, one tail, and two arm domains (Figure 1A; Ferbitz et al., 2004Ferbitz L. Maier T. Patzelt H. Bukau B. Deuerling E. Ban N. Nature. 2004; 431: 590-596Crossref PubMed Scopus (290) Google Scholar). The ribosomal binding site for TF was determined using similar strategy. A crystal structure of TF ribosome-binding domain (the tail) in complex with 50S subunits, positioned TF between domain III of 23S RNA and ribosomal proteins L23 and L29 (Ferbitz et al., 2004Ferbitz L. Maier T. Patzelt H. Bukau B. Deuerling E. Ban N. Nature. 2004; 431: 590-596Crossref PubMed Scopus (290) Google Scholar, Baram et al., 2005Baram D. Pyetan E. Sittner A. Auerbach-Nevo T. Bashan A. Yonath A. Proc. Natl. Acad. Sci. USA. 2005; 102: 12017-12022Crossref PubMed Scopus (87) Google Scholar). Here, the other domains of TF extend over the tunnel exit, forming a hydrophobic “cradle,” large enough to accommodate folding of an entire protein domain. Interestingly, this implies that PDF and TF can bind the ribosome simultaneously and that the N-terminal tail of the newly-synthesized protein may be shuttled to PDF while shielded by TF (Bingel-Erlenmeyer et al., 2008Bingel-Erlenmeyer R. Kohler R. Kramer G. Sandikci A. Antolic S. Maier T. Schaffitzel C. Wiedmann B. Bukau B. Ban N. A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing.Nature. 2008https://doi.org/10.1038/nature06683Crossref Scopus (78) Google Scholar). There are also indications that methionine aminopeptidase (MAP) binds on the other side of TF (Bingel-Erlenmeyer et al., 2008Bingel-Erlenmeyer R. Kohler R. Kramer G. Sandikci A. Antolic S. Maier T. Schaffitzel C. Wiedmann B. Bukau B. Ban N. A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing.Nature. 2008https://doi.org/10.1038/nature06683Crossref Scopus (78) Google Scholar, Addlagatta et al., 2005Addlagatta A. Quillin M.L. Omotoso O. Liu J.O. Matthews B.W. Biochemistry. 2005; 44: 7166-7174Crossref PubMed Scopus (46) Google Scholar). Signal recognition particle (SRP) binds to translating ribosomes, to scan the nascent chains for hydrophobic signal sequences, which target proteins for membrane insertion. When SRP detects a signal sequence, it binds to it 1000-fold more tightly, allowing subsequent association with an SRP receptor, FtsY, and finally binding to a protein conducting channel, SecYEG, thus mediating cotranslational insertion into a membrane. The bacterial SRP consists of the 4.5S RNA and a 50 kDa three domain protein, Ffh. Cryo-EM reconstruction of the E. coli SRP bound to a ribosome carrying a nascent chain signal sequence (Schaffitzel et al., 2006Schaffitzel C. Oswald M. Berger I. Ishikawa T. Abrahams J.P. Koerten H.K. Koning R.I. Ban N. Nature. 2006; 444: 503-506Crossref PubMed Scopus (103) Google Scholar) revealed that SRP forms an elongated molecule, with four areas of contact with the ribosome (Figure 1B). Details of these contacts were dissected by docking of 70S ribosome and individual Ffh domains crystal structures: N-terminal domain contacts L23 and L29; M domain contacts helix 24 of 23S RNA; 4.5S RNA contacts L32; and in order to form a 4th contact surface, helix 59 of 23S RNA moves about 9 Å toward SRP and contacts M domain. In the absence of a signal sequence, only the first contact is formed, and in this “scanning” state, SRP binding may be compatible with the binding of the TF anchor domain (Schaffitzel et al., 2006Schaffitzel C. Oswald M. Berger I. Ishikawa T. Abrahams J.P. Koerten H.K. Koning R.I. Ban N. Nature. 2006; 444: 503-506Crossref PubMed Scopus (103) Google Scholar, Eisner et al., 2006Eisner G. Moser M. Schafer U. Beck K. Muller M. J. Biol. Chem. 2006; 281: 7172-7179Crossref PubMed Scopus (22) Google Scholar). When the ribosomal SRP complex associates with the membrane-bound receptor, FtsY, SRP releases the signal sequence, transferring it into the SecYEG channel. This complex consists of three different polypeptides, and the crystal structure of an archaeal SecYEG complex showed that the pore consists of two linked halves. The pore is closed by a “plug” helix that gets displaced by the signal sequence, creating an hour-glass shape with a hydrophobic seal around the translocated polypeptide (Van den Berg et al., 2004Van den Berg B. Clemons Jr., W.M. Collinson I. Modis Y. Hartmann E. Harrison S.C. Rapoport T.A. Nature. 2004; 427: 36-44Crossref PubMed Scopus (921) Google Scholar). Secreted proteins will pass through the hydrophilic pore of the channel entirely while transmembrane segments of integral membrane proteins exit through a lateral gate into the lipid phase. EM reconstruction of a translating ribosome in complex with SecYEG displays three contact areas around the exit tunnel, leaving a large opening where the polypeptide is accessible. SecYEG interacts with 23S RNA helices 59 and 24 and SecG contacts L23 and L29 (Mitra et al., 2005Mitra K. Schaffitzel C. Shaikh T. Tama F. Jenni S. Brooks 3rd, C.L. Ban N. Frank J. Nature. 2005; 438: 318-324Crossref PubMed Scopus (214) Google Scholar). SecYEG can dimerize, but the functional oligomeric state is a matter of debate; the crystal structure suggests that a single SecYEG complex forms a pore (Van den Berg et al., 2004Van den Berg B. Clemons Jr., W.M. Collinson I. Modis Y. Hartmann E. Harrison S.C. Rapoport T.A. Nature. 2004; 427: 36-44Crossref PubMed Scopus (921) Google Scholar), while EM reconstructions suggest that the pores of two SecYEG complexes can fuse (Mitra et al., 2005Mitra K. Schaffitzel C. Shaikh T. Tama F. Jenni S. Brooks 3rd, C.L. Ban N. Frank J. Nature. 2005; 438: 318-324Crossref PubMed Scopus (214) Google Scholar). Therefore, the space surrounding the translating ribosome exit tunnel could be considered to be a “prime” location, a functionally relevant docking site for number of factors, acting on nascent polypeptide chain downstream from the ribosome. What is biochemically known about how these proteins compete for ribosome binding? TF is the most abundant of the proteins and is expected to be almost stoichiometrically bound to ribosomes (Kaiser et al., 2006Kaiser C.M. Chang H.C. Agashe V.R. Lakshmipathy S.K. Etchells S.A. Hayer-Hartl M. Hartl F.U. Barral J.M. Nature. 2006; 444: 455-460Crossref PubMed Scopus (174) Google Scholar). On the other hand, PDF binds ribosomes with micromolar affinity, which is in the same range as its cellular concentration, suggesting that PDF shares its time between many ribosomes. SRP and TF appear to be capable of simultaneous binding to the ribosome, but can also both displace each other from a nascent chain (Eisner et al., 2006Eisner G. Moser M. Schafer U. Beck K. Muller M. J. Biol. Chem. 2006; 281: 7172-7179Crossref PubMed Scopus (22) Google Scholar). The combined use of biochemistry, X-ray crystallography, and cryo-EM has been essential to achieve the present structural understanding of these systems. Higher resolution crystal structures allowed the identification of interactions in lower resolution EM reconstructions, and cocrystal structures of ribosomes with the ribosome-binding domains, like the one presented in the study by Bingel-Erlenmeyer et al., has increased the level of interpretation. Purification methods for defined stalled ribosomal nascent-chain complexes have been of fundamental importance for these studies. Still, many questions remain to fully understand how a new protein is processed and targeted, not to mention how it co- and posttranslationally reaches its final folded state. Interactions of the peptide with the interior of the ribosomal tunnel may also play an important role in these processes." @default.
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• W2045939425 title "Exit Biology: Battle for the Nascent Chain" @default.
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