SRP Keeps Polypeptides Translocation-competent by Slowing Translation to Match Limiting ER-targeting Sites

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2008 May 6

PMID 18455985

Citations 81

Authors

Asvin K K Lakkaraju

Camille Mary

Anne Scherrer

Arthur E Johnson

Katharina Strub

Affiliations

Soon will be listed here.

Abstract

SRP is essential for targeting nascent chains to the endoplasmic reticulum, and it delays nascent chain elongation in cell-free translation systems. However, the significance of this function has remained unclear. We show that efficient protein translocation into the ER is incompatible with normal cellular translation rates due to rate-limiting concentrations of SRP receptor (SR). We complemented mammalian cells depleted of SRP14 by expressing mutant versions of the protein lacking the elongation arrest function. The absence of a delay caused inefficient targeting of preproteins leading to defects in secretion, depletion of proteins in the endogenous membranes, and reduced cell growth. The detrimental effects were reversed by either reducing the cellular protein synthesis rate or increasing SR expression. SRP therefore ensures that nascent chains remain translocation competent during the targeting time window dictated by SR. Since SRP-signal sequence affinities vary, the delay may also regulate which proteins are preferentially targeted.

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References

Flanagan J, Chen J, Miao Y, Shao Y, Lin J, Bock P . Signal recognition particle binds to ribosome-bound signal sequences with fluorescence-detected subnanomolar affinity that does not diminish as the nascent chain lengthens. J Biol Chem. 2003; 278(20):18628-37. DOI: 10.1074/jbc.M300173200. View

Halic M, Becker T, Pool M, Spahn C, Grassucci R, Frank J . Structure of the signal recognition particle interacting with the elongation-arrested ribosome. Nature. 2004; 427(6977):808-14. DOI: 10.1038/nature02342. View

Goder V, Crottet P, Spiess M . In vivo kinetics of protein targeting to the endoplasmic reticulum determined by site-specific phosphorylation. EMBO J. 2000; 19(24):6704-12. PMC: 366643. DOI: 10.1093/emboj/19.24.6704. View

Mason N, Ciufo L, Brown J . Elongation arrest is a physiologically important function of signal recognition particle. EMBO J. 2000; 19(15):4164-74. PMC: 306590. DOI: 10.1093/emboj/19.15.4164. View

Walter P, Blobel G . Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specific arrest of chain elongation that is released by microsomal membranes. J Cell Biol. 1981; 91(2 Pt 1):557-61. PMC: 2111983. DOI: 10.1083/jcb.91.2.557. View

Shan S, Stroud R, Walter P . Mechanism of association and reciprocal activation of two GTPases. PLoS Biol. 2004; 2(10):e320. PMC: 517823. DOI: 10.1371/journal.pbio.0020320. View

Okun M, Shields D . Translocation of preproinsulin across the endoplasmic reticulum membrane. The relationship between nascent polypeptide size and extent of signal recognition particle-mediated inhibition of protein synthesis. J Biol Chem. 1992; 267(16):11476-82. View

Wolin S, Walter P . Ribosome pausing and stacking during translation of a eukaryotic mRNA. EMBO J. 1988; 7(11):3559-69. PMC: 454858. DOI: 10.1002/j.1460-2075.1988.tb03233.x. View

Terzi L, Pool M, Dobberstein B, Strub K . Signal recognition particle Alu domain occupies a defined site at the ribosomal subunit interface upon signal sequence recognition. Biochemistry. 2004; 43(1):107-17. DOI: 10.1021/bi0353777. View

10.

Wiedmann M, Kurzchalia T, BIELKA H, Rapoport T . Direct probing of the interaction between the signal sequence of nascent preprolactin and the signal recognition particle by specific cross-linking. J Cell Biol. 1987; 104(2):201-8. PMC: 2114417. DOI: 10.1083/jcb.104.2.201. View

11.

Schaletzky J, Rapoport T . Ribosome binding to and dissociation from translocation sites of the endoplasmic reticulum membrane. Mol Biol Cell. 2006; 17(9):3860-9. PMC: 1593163. DOI: 10.1091/mbc.e06-05-0439. View

12.

Guth S, Volzing C, Muller A, Jung M, Zimmermann R . Protein transport into canine pancreatic microsomes: a quantitative approach. Eur J Biochem. 2004; 271(15):3200-7. DOI: 10.1111/j.1432-1033.2004.04252.x. View

13.

Huck L, Scherrer A, Terzi L, Johnson A, Bernstein H, Cusack S . Conserved tertiary base pairing ensures proper RNA folding and efficient assembly of the signal recognition particle Alu domain. Nucleic Acids Res. 2004; 32(16):4915-24. PMC: 519120. DOI: 10.1093/nar/gkh837. View

14.

Pool M . Signal recognition particles in chloroplasts, bacteria, yeast and mammals (review). Mol Membr Biol. 2005; 22(1-2):3-15. DOI: 10.1080/09687860400026348. View

15.

Rapoport T, Heinrich R, Walter P, Schulmeister T . Mathematical modeling of the effects of the signal recognition particle on translation and translocation of proteins across the endoplasmic reticulum membrane. J Mol Biol. 1987; 195(3):621-36. DOI: 10.1016/0022-2836(87)90186-0. View

16.

SIEGEL V, Walter P . Elongation arrest is not a prerequisite for secretory protein translocation across the microsomal membrane. J Cell Biol. 1985; 100(6):1913-21. PMC: 2113602. DOI: 10.1083/jcb.100.6.1913. View

17.

Johnsson N, Varshavsky A . Split ubiquitin as a sensor of protein interactions in vivo. Proc Natl Acad Sci U S A. 1994; 91(22):10340-4. PMC: 45015. DOI: 10.1073/pnas.91.22.10340. View

18.

Blau M, Mullapudi S, Becker T, Dudek J, Zimmermann R, Penczek P . ERj1p uses a universal ribosomal adaptor site to coordinate the 80S ribosome at the membrane. Nat Struct Mol Biol. 2005; 12(11):1015-6. DOI: 10.1038/nsmb998. View

19.

SIEGEL V, Walter P . Removal of the Alu structural domain from signal recognition particle leaves its protein translocation activity intact. Nature. 1986; 320(6057):81-4. DOI: 10.1038/320081a0. View

20.

Keenan R, Freymann D, Stroud R, Walter P . The signal recognition particle. Annu Rev Biochem. 2001; 70:755-75. DOI: 10.1146/annurev.biochem.70.1.755. View