Ribosome crystallography: catalysis and evolution of peptide-bond formation, nascent chain elongation and its co-translational folding

Bashan, Anat; Yonath, Ada

doi:10.1042/bst0330488

Cited by 17 publications

(14 citation statements)

References 34 publications

(62 reference statements)

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“…The nascent proteins move out of the ribosome via an exit tunnel whose opening lies adjacent to the PTC and receives thereby each successive peptide bond as the protein elongates. Thus the architecture of the ribosome is consistent with the requirements of peptide bond catalysis and protein formation [2, 3,5,9,10].Given the structural architecture of the ribosome, quantum crystallography (QCr) [11] may be applied to study the transition state (TS) for peptide bond formation. (The foundations and applications of QCr are reviewed in Chapter 1.)…”

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Quantum Transition State for Peptide Bond Formation in the Ribosome

Massa

Matta

Yonath

et al. 2010

Quantum Biochemistry

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Crystallography is the principal method used to determine the structure of a ribosome, and consequently for understanding its functions, including formation of the peptide bond by ribozyme catalysis, and the decoding of the genetic code [1][2][3][4][5]. As shown in Figure 16.1, the ribosome is made of two subunits. It was found that the mRNA is decoded at the small subunit. The peptide bond is formed on the larger subunit within a cavity, hosting the peptidyl transferase center (PTC), composed mainly of ribosomal RNA [1][2][3][4][5][6][7][8].Of importance to the quantum calculations reviewed in this chapter, a region of pseudo twofold symmetry, which was detected in all known ribosome structures in and around the PTC [1,3b,3c,3d,3e], is associated with the translocation of the aminoacylated tRNA through the ribosome, as peptide bond formation occurs [2, 3], navigated by the ribosome architecture ( Figure 16.2). The nascent proteins move out of the ribosome via an exit tunnel whose opening lies adjacent to the PTC and receives thereby each successive peptide bond as the protein elongates. Thus the architecture of the ribosome is consistent with the requirements of peptide bond catalysis and protein formation [2, 3,5,9,10].Given the structural architecture of the ribosome, quantum crystallography (QCr) [11] may be applied to study the transition state (TS) for peptide bond formation. (The foundations and applications of QCr are reviewed in Chapter 1.) QCr combines crystallographic structural information with quantum mechanical theory. This facilitates theoretical calculations and adds an energetic aspect to crystallography. The crystallographic structure is a starting point, constraint and anchor for the quantum calculations. In QCr the molecular system is mathematically divided into computationally tractable pieces. Subsequently, this may be followed by a quantum investigation of their mutual interactions, and thus in a step-by-step manner one may rebuild the entire quantum mechanism as a whole. This approach has been applied to the investigation of the peptide bond TS. The first step here was to Quantum Biochemistry. Edited by Chérif F. Matta

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Quantum Transition State for Peptide Bond Formation in the Ribosome

Massa

Matta

Yonath

et al. 2010

Quantum Biochemistry

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“…The nascent proteins are directed by the rotatory motion into the exit tunnel at extended conformation, fitting the tunnel's narrow opening. Hence, the ribosomal architecture provides all of the positional elements required for amino acid polymerization (2,3,9).…”

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The transition state for formation of the peptide bond in the ribosome

Gindulytė

Bashan

Agmon

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Using quantum mechanics and exploiting known crystallographic coordinates of tRNA substrate located in the ribosome peptidyl transferase center around the 2-fold axis, we have investigated the mechanism for peptide-bond formation. The calculation is based on a choice of 50 atoms assumed to be important in the mechanism. We used density functional theory to optimize the geometry and energy of the transition state (TS) for peptide-bond formation. The TS is formed simultaneously with the rotatory motion enabling the translocation of the A-site tRNA 3′ end into the P site, and we estimated the magnitude of rotation angle between the A-site starting position and the place at which the TS occurs. The calculated TS activation energy, E a , is 35.5 kcal (1 kcal = 4.18 kJ)/mol, and the increase in hydrogen bonding between the rotating A-site tRNA and ribosome nucleotides as the TS forms appears to stabilize it to a value qualitatively estimated to be ≈18 kcal/mol. The optimized geometry corresponds to a structure in which the peptide bond is being formed as other bonds are being broken, in such a manner as to release the P-site tRNA so that it may exit as a free molecule and be replaced by the translocating A-site tRNA. At TS formation the 2′ OH group of the P-site tRNA A76 forms a hydrogen bond with the oxygen atom of the carboxyl group of the amino acid attached to the A-site tRNA, which may be indicative of its catalytic role, consistent with recent biochemical experiments.

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“…At the next steps, the deacylated tRNA from the P-site exits the ribosome through the E-site, the A-site tRNA is translocated to the P-site, and the nascent peptide is guided to the protein exit tunnel. Structural studies of ribosomal particles and of their complexes with substrate mimics [12–15] have revealed that as the peptidylated tRNA translocates from the A-site to P-site, it undergoes a nearly 180° rotation of its 3′-end [13]. This motion appears to be necessary for positioning the A-site nucleophilic amine and the P-site carbonyl carbon within the distance and into the topology that allow the transition state of the peptide bond to form, and may also be required for sending the nascent proteins into the exit tunnel [13–15].…”

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Rotational restriction of nascent peptides as an essential element of co-translational protein folding: possible molecular players and structural consequences

Sorokina¹,

Mushegian²

2017

Biol Direct

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BackgroundA basic tenet of protein science is that all information about the spatial structure of proteins is present in their sequences. Nonetheless, many proteins fail to attain native structure upon experimental denaturation and refolding in vitro, raising the question of the specific role of cellular machinery in protein folding in vivo. Recently, we hypothesized that energy-dependent twisting of the protein backbone is an unappreciated essential factor guiding the protein folding process in vivo. Torque force may be applied by the ribosome co-translationally, and when accompanied by simultaneous restriction of the rotational mobility of the distal part of the growing chain, the resulting tension in the protein backbone would facilitate the formation of local secondary structure and direct the folding process.ResultsOur model of the early stages of protein folding in vivo postulates that the free motion of both terminal regions of the protein during its synthesis and maturation is restricted. The long-known but unexplained phenomenon of statistical overrepresentation of protein termini on the surfaces of the protein structures may be an indication of the backbone twist-based folding mechanism; sustained maintenance of a twist requires that both ends of the protein chain are anchored in space, and if the ends are released only after the majority of folding is complete, they are much more likely to remain on the surface of the molecule. We identified the molecular components that are likely to play a role in the twisting of the nascent protein chain and in the anchoring of its N-terminus. The twist may be induced at the C-terminus of the nascent polypeptide by the peptidyltransferase center of the ribosome. Several ribosome-associated proteins, including the trigger factor in bacteria and the nascent polypeptide-associated complex in archaea and eukaryotes, may restrict the rotational mobility of the N-proximal regions of the peptides.ConclusionsMany experimental observations are consistent with the hypothesis of co-translational twisting of the protein backbone. Several molecular players in this hypothetical mechanism of protein folding can be suggested. In addition, the new view of protein folding in vivo opens the possibility of novel potential drug targets to combat human protein folding diseases.ReviewersThis article was reviewed by Lakshminarayan Iyer and István Simon.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-017-0186-1) contains supplementary material, which is available to authorized users.

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Ribosome crystallography: catalysis and evolution of peptide-bond formation, nascent chain elongation and its co-translational folding

Cited by 17 publications

References 34 publications

Quantum Transition State for Peptide Bond Formation in the Ribosome

Quantum Transition State for Peptide Bond Formation in the Ribosome

The transition state for formation of the peptide bond in the ribosome

Rotational restriction of nascent peptides as an essential element of co-translational protein folding: possible molecular players and structural consequences

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