SRP-dependent cotranslational protein targeting to membrane (Homo sapiens)
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Description
The process for translation of a protein destined for the endoplasmic reticulum (ER) branches from the canonical cytoslic translation process at the point when a nascent polypeptide containing a hydrophobic signal sequence is exposed on the surface of the cytosolic ribosome:mRNA:peptide complex. The signal sequence mediates the interaction of this complex with a cytosolic signal recognition particle (SRP) to form a complex which in turn docks with an SRP receptor complex on the ER membrane. There the ribosome complex is transferred from the SRP complex to a translocon complex embedded in the ER membrane and reoriented so that the nascent polypeptide protrudes through a pore in the translocon into the ER lumen. Translation, which had been halted by SRP binding, now resumes, the signal peptide is cleaved from the polypeptide, and elongation proceeds, with the growing polypeptide oriented into the ER lumen.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1799339
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- Yin J, Yang CH, Zwieb C.; ''Assembly of the human signal recognition particle (SRP): overlap of regions required for binding of protein SRP54 and assembly control.''; PubMed Europe PMC Scholia
- Menichelli E, Isel C, Oubridge C, Nagai K.; ''Protein-induced conformational changes of RNA during the assembly of human signal recognition particle.''; PubMed Europe PMC Scholia
- Skach WR.; ''The expanding role of the ER translocon in membrane protein folding.''; PubMed Europe PMC Scholia
- Zwieb C.; ''Recognition of a tetranucleotide loop of signal recognition particle RNA by protein SRP19.''; PubMed Europe PMC Scholia
- Römisch K, Miller FW, Dobberstein B, High S.; ''Human autoantibodies against the 54 kDa protein of the signal recognition particle block function at multiple stages.''; PubMed Europe PMC Scholia
- Rose MA, Weeks KM.; ''Visualizing induced fit in early assembly of the human signal recognition particle.''; PubMed Europe PMC Scholia
- Lakkaraju AK, Mary C, Scherrer A, Johnson AE, Strub K.; ''SRP keeps polypeptides translocation-competent by slowing translation to match limiting ER-targeting sites.''; PubMed Europe PMC Scholia
- Iakhiaeva E, Hinck CS, Hinck AP, Zwieb C.; ''Characterization of the SRP68/72 interface of human signal recognition particle by systematic site-directed mutagenesis.''; PubMed Europe PMC Scholia
- Hsu K, Chang DY, Maraia RJ.; ''Human signal recognition particle (SRP) Alu-associated protein also binds Alu interspersed repeat sequence RNAs. Characterization of human SRP9.''; PubMed Europe PMC Scholia
- Yin J, Iakhiaeva E, Menichelli E, Zwieb C.; ''Identification of the RNA binding regions of SRP68/72 and SRP72 by systematic mutagenesis of human SRP RNA.''; PubMed Europe PMC Scholia
- Gowda K, Clemons WM, Zwieb C, Black SD.; ''Expression, purification, and crystallography of the conserved methionine-rich domain of human signal recognition particle 54 kDa protein.''; PubMed Europe PMC Scholia
- Nagai K, Oubridge C, Kuglstatter A, Menichelli E, Isel C, Jovine L.; ''Structure, function and evolution of the signal recognition particle.''; PubMed Europe PMC Scholia
- Egea PF, Stroud RM, Walter P.; ''Targeting proteins to membranes: structure of the signal recognition particle.''; PubMed Europe PMC Scholia
- Merrick WC.; ''Eukaryotic protein synthesis: still a mystery.''; PubMed Europe PMC Scholia
- Kuglstatter A, Oubridge C, Nagai K.; ''Induced structural changes of 7SL RNA during the assembly of human signal recognition particle.''; PubMed Europe PMC Scholia
- Potter MD, Nicchitta CV.; ''Endoplasmic reticulum-bound ribosomes reside in stable association with the translocon following termination of protein synthesis.''; PubMed Europe PMC Scholia
- Dodson G, Steiner D.; ''The role of assembly in insulin's biosynthesis.''; PubMed Europe PMC Scholia
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 80S ribosome | REACT_115572 (Reactome)  | |||
| REACT_115572 (Reactome) | The synthesis of a protein destined for the endoplasmic reticulum starts with the canonical events of cytosolic translation initiation and proceeds to the point where a nascent polypeptide chain containing a signal sequence protrudes from the mRNA:ribosome complex. Merrick (2010) provides an overview of these events. | |||
| REACT_115582 (Reactome) | The Signal Recognition Particle (SRP) receptor mediates transfer of the ribosome:mRNA:nascent protein complex to the Translocon Complex. A coupled reaction (not annotated here) in which GTP molecules are hydrolyzed by the alpha subunit of the SRP Receptor and the SRP54 subunit of the SRP is thought to ensure release of the SRP only after the ribosome is properly reoriented. At the end of this process, the ribosome is attached to the endoplasmic reticulum (ER) membrane with its associated nascent polypeptide protruding through the Translocon Complex into the ER lumen. | |||
| REACT_115742 (Reactome) | As the signal peptide of the nascent protein enters the lumen of the endoplasmic reticulum (ER), the signal peptide is recognized and cleaved by the ER membrane-associated Signal Peptidase. Translation of the protein then proceeds to completion. | |||
| REACT_115921 (Reactome) | The Ribosome Nascent Complex containing the ribosome and protruding signal peptide of preprolactin is bound by the Signal Recognition Particle Complex. Translation is paused during this step. | |||
| REACT_116124 (Reactome) | The SRP receptor in the the endoplasmic reticulum (ER) membrane binds via its alpha subunit to the the SRP54 subunit of the Signal Recognition Particle (SRP), which itself is bound to a ribosome:mRNA:polypeptide complex. This interaction tethers the ribosome to the ER membrane, oriented so that the nacent polypeptide will traverse the ER membrane and enter the ER lumen. This process has been characterized in detail in cultured canine cells; this human event is inferred by homology from its canine counterpart. | |||
| SRP
polypeptide+signal ribosome | REACT_116124 (Reactome) | |||
| SRP receptor
SRP ribosome polypeptide+signal | REACT_115582 (Reactome) | |||
| SRP receptor | Arrow | REACT_115582 (Reactome) | ||
| SRP receptor | REACT_116124 (Reactome) | |||
| Signal Peptidase | mim-catalysis | REACT_115742 (Reactome) | ||
| Signal Recognition Particle | Arrow | REACT_115582 (Reactome) | ||
| Signal Recognition Particle | REACT_115921 (Reactome) | |||
| Translocon TRAP | REACT_115582 (Reactome) | |||
| cleaved polypeptide Translocon | Arrow | REACT_115742 (Reactome) | ||
| mRNA | REACT_115572 (Reactome) | |||
| polypeptide+signal Translocon | Arrow | REACT_115582 (Reactome) | ||
| ribosome
mRNA polypeptide+signal | REACT_115921 (Reactome) | |||
| signal peptide | Arrow | REACT_115742 (Reactome) |
