Mathematical modeling of the effects of the signal recognition particle on translation and translocation of proteins across the endoplasmic reticulum membrane

Rapoport, Tom A.; Heinrich, Reinhart; Walter, Peter; Schulmeister, Thomas

doi:10.1016/0022-2836(87)90186-0

Cited by 44 publications

(23 citation statements)

References 29 publications

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“…Similar observations were made either when the SRP subunits were depleted, or when the kinetics of SRP-receptor binding was compromised (96, 157). These data support the earlier proposals by Gierasch (164) and Rapoport (114) in which co-translational protein targeting is in kinetic competition with ongoing translation and contributes to substrate selection by the SRP.…”

Section: Sequential Checkpoints Govern Fidelity Of Co-translational Psupporting

confidence: 91%

Fidelity of Cotranslational Protein Targeting by the Signal Recognition Particle

Zhang

Shan

2014

Annu. Rev. Biophys.

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Accurate folding, assembly, localization and maturation of newly synthesized proteins are essential to all cells and requires a high fidelity in the protein biogenesis machineries that mediate these processes. Here, we review our current understanding on how high fidelity is achieved in one of these processes, the co-translational targeting of nascent membrane and secretory proteins by the signal recognition particle (SRP). Recent biochemical, biophysical, and structural studies have elucidated how the correct substrates drive a series of elaborate conformational rearrangements in the SRP and SRP receptor GTPases, which provide effective fidelity checkpoints to reject incorrect substrates and enhance the fidelity of this essential cellular pathway. The mechanisms used by the SRP to ensure fidelity share important conceptual analogies with those used by cellular machineries involved in DNA replication, transcription and translation, and likely represent general principles for other complex cellular pathways.

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Section: Sequential Checkpoints Govern Fidelity Of Co-translational Psupporting

confidence: 91%

Fidelity of Cotranslational Protein Targeting by the Signal Recognition Particle

Zhang

Shan

2014

Annu. Rev. Biophys.

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“…The data presented here indicate that integration of the M2 protein of influenza A virus into the ER was strictly dependent upon the signal recognition particle. High affinity binding of SRP to signal sequences can induce a complete arrest (50) or substantial decrease in the protein synthesis elongation rate (21), and in so doing effectively increase the time window for interaction of the SRP-ribosome complex with the ER membrane (37). Neither an arrest of translation nor a pronounced inhibition of M2 synthesis was detected in a 1-h translation containing SRP (data not shown).…”

Section: Discussionmentioning

confidence: 96%

Integration of a small integral membrane protein, M2, of influenza virus into the endoplasmic reticulum: analysis of the internal signal-anchor domain of a protein with an ectoplasmic NH2 terminus.

Hull

Gilmore

Lamb

1988

The Journal of Cell Biology

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Abstract. The M2 protein of influenza A virus is a small integral membrane protein of 97 residues that is expressed on the surface of virus-infected cells. M2 has an unusual structure as it lacks a cleavable signal sequence yet contains an ectoplasmic amino-terminal domain of 23 residues, a 19 residue hydrophobic transmembrane spanning segment, and a cytoplasmic carboxyl-terminal domain of 55 residues. Oligonucleotidemediated deletion mutagenesis was used to construct a series of M2 mutants lacking portions of the hydrophobic segment. Membrane integration of the M2 protein was examined by in vitro translation of synthetic mRNA transcripts prepared using bacteriophage T7 RNA polymerase. After membrane integration, M2 was resistant to alkaline extraction and was converted to an Mr --~ 7,000 membrane-protected fragment after digestion with trypsin. In vitro integration of M2 requires the cotranslational presence of the signal recognition particle. Deletion of as few as two residues from the hydrophobic segment of M2 markedly decreases the efficiency of membrane integration, whereas deletion of six residues completely eliminates integration. M2 proteins containing deletions that eliminate stable membrane anchoring are apparently not recognized by signal recognition particles, as these polypeptides remain sensitive to protease digestion, indicating that in addition they do not have a functional signal sequence. These data thus indicate that the signal sequence that initiates membrane integration of M2 resides within the transmembrane spanning segment of the polypeptide.

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“…This variation in efficiency can be explained by Rapoport's model for the interaction of a signal sequence with the signal recognition particle (SRP) (31), in which this interaction is postulated as an equilibrium between unbound SRP on one hand and the SRPsignal complex on the other. Thus SRP can have different binding affinities for different signals, and in the case of a poor signal, binding to the SRP might not occur until a significant increase in the signal concentration kinetically favors the formation of the SRP-signal complex.…”

Section: Discussionmentioning

confidence: 99%

Proteinase Inhibitor 6 Cannot Be Secreted, Which Suggests It Is a New Type of Cellular Serpin

Scott

Coughlin

Bird

et al. 1996

Journal of Biological Chemistry

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We have recently described a new serine proteinase inhibitor, proteinase inhibitor 6 (PI-6). This serpin has features that suggest it may function intracellularly, but its close resemblance to ovalbumin serpins like plasminogen activator inhibitor 2 (PAI-2) raises the possibility that it is secreted to regulate an extracellular proteinase. To determine whether PI-6 is secreted, we have examined its cellular distribution by immunohistochemistry and have attempted to induce its release from platelets and from cultured cells. We find that PI-6 is present in endothelial and epithelial cells, but it is apparently cytoplasmic and it is not released from cells in response to phorbol ester, dibutyryl cAMP or tumor necrosis factor ␣ treatment. It is also not released from activated platelets. The addition of a conventional signal peptide to the amino terminus of PI-6 directed its translocation into the endoplasmic reticulum (ER), resulting in glycosylation but not secretion of the molecule. By contrast, the addition of the same signal peptide to PAI-2 markedly enhanced its translocation and secretion. Glycosylated PI-6 was sequestered in the ER and was incapable of interacting with thrombin. The failure of PI-6 to move along the secretory pathway, and the loss of inhibitory function of ER-localized PI-6, demonstrates that unlike PAI-2, PI-6 is not naturally secreted. Taken together, these results suggest that PI-6 has evolved to fulfil an intracellular role and that it represents a new type of cellular serpin.

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Mathematical modeling of the effects of the signal recognition particle on translation and translocation of proteins across the endoplasmic reticulum membrane

Cited by 44 publications

References 29 publications

Fidelity of Cotranslational Protein Targeting by the Signal Recognition Particle

Fidelity of Cotranslational Protein Targeting by the Signal Recognition Particle

Integration of a small integral membrane protein, M2, of influenza virus into the endoplasmic reticulum: analysis of the internal signal-anchor domain of a protein with an ectoplasmic NH2 terminus.

Proteinase Inhibitor 6 Cannot Be Secreted, Which Suggests It Is a New Type of Cellular Serpin

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