Letter | Published:

Following the signal sequence from ribosomal tunnel exit to signal recognition particle

Nature volume 444, pages 507511 (23 November 2006) | Download Citation



Membrane and secretory proteins can be co-translationally inserted into or translocated across the membrane1. This process is dependent on signal sequence recognition on the ribosome by the signal recognition particle (SRP), which results in targeting of the ribosome–nascent-chain complex to the protein-conducting channel at the membrane2,3. Here we present an ensemble of structures at subnanometre resolution, revealing the signal sequence both at the ribosomal tunnel exit and in the bacterial and eukaryotic ribosome–SRP complexes. Molecular details of signal sequence interaction in both prokaryotic and eukaryotic complexes were obtained by fitting high-resolution molecular models. The signal sequence is presented at the ribosomal tunnel exit in an exposed position ready for accommodation in the hydrophobic groove of the rearranged SRP54 M domain. Upon ribosome binding, the SRP54 NG domain also undergoes a conformational rearrangement, priming it for the subsequent docking reaction with the NG domain of the SRP receptor. These findings provide the structural basis for improving our understanding of the early steps of co-translational protein sorting.

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  1. 1.

    , , & Biogenesis of inner membrane proteins in Escherichia coli.. Annu. Rev. Microbiol. 59, 329–355 (2005)

  2. 2.

    & SRP-mediated protein targeting: structure and function revisited. Biochim. Biophys. Acta 1694, 17–35 (2004)

  3. 3.

    & The signal recognition particle and its interactions during protein targeting. Curr. Opin. Struct. Biol. 15, 116–125 (2005)

  4. 4.

    et al. Structure of the signal recognition particle interacting with the elongation-arrested ribosome. Nature 427, 808–814 (2004)

  5. 5.

    et al. Interplay of signal recognition particle and trigger factor at L23 near the nascent chain exit site on the Escherichia coli ribosome. J. Cell Biol. 161, 679–684 (2003)

  6. 6.

    , & A method of focused classification, based on the bootstrap 3D variance analysis, and its application to EF-G-dependent translocation. J. Struct. Biol. 154, 184–194 (2006)

  7. 7.

    et al. Incorporation of aminoacyl-tRNA into the ribosome as seen by cryo-electron microscopy. Nature Struct. Biol. 10, 899–906 (2003)

  8. 8.

    , & Nascent membrane and secretory proteins differ in FRET-detected folding far inside the ribosome and in their exposure to ribosomal proteins. Cell 116, 725–736 (2004)

  9. 9.

    & Secondary structure formation of a transmembrane segment in Kv channels. Biochemistry 44, 8230–8243 (2005)

  10. 10.

    , , & Early encounters of a nascent membrane protein: specificity and timing of contacts inside and outside the ribosome. J. Cell Biol. 170, 27–35 (2005)

  11. 11.

    et al. 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. 278, 18628–18637 (2003)

  12. 12.

    , , , & Alternate recruitment of signal recognition particle and trigger factor to the signal sequence of a growing nascent polypeptide. J. Biol. Chem. 281, 7172–7179 (2006)

  13. 13.

    , , , & Crystal structure of the ribonucleoprotein core of the signal recognition particle. Science 287, 1232–1239 (2000)

  14. 14.

    , , & Crystal structure of the complete core of archaeal signal recognition particle and implications for interdomain communication. Proc. Natl Acad. Sci. USA 100, 14701–14706 (2003)

  15. 15.

    et al. Conformations of the signal recognition particle protein Ffh from Escherichia coli as determined by FRET. J. Mol. Biol. 351, 417–430 (2005)

  16. 16.

    , , , & Distinct modes of signal recognition particle interaction with the ribosome. Science 297, 1345–1348 (2002)

  17. 17.

    et al. The binding mode of the trigger factor on the ribosome: implications for protein folding and SRP interaction. Structure 13, 1685–1694 (2005)

  18. 18.

    , , & SRP meets the ribosome. Nature Struct. Mol. Biol. 11, 1049–1053 (2004)

  19. 19.

    et al. Model for signal sequence recognition from amino-acid sequence of 54K subunit of signal recognition particle. Nature 340, 482–486 (1989)

  20. 20.

    et al. Substrate twinning activates the signal recognition particle and its receptor. Nature 427, 215–221 (2004)

  21. 21.

    , , & Heterodimeric GTPase core of the SRP targeting complex. Science 303, 373–377 (2004)

  22. 22.

    et al. Signal recognition particle receptor exposes the ribosomal translocon binding site. Science 312, 745–747 (2006)

  23. 23.

    & Co-translational protein targeting catalyzed by the Escherichia coli signal recognition particle and its receptor. EMBO J. 16, 4880–4886 (1997)

  24. 24.

    , & Electron microscopy and computer image averaging of ice-embedded large ribosomal subunits from Escherichia coli.. J. Mol. Biol. 199, 137–147 (1988)

  25. 25.

    et al. SPIDER and WEB: processing and visualization of images in 3D electron microscopy and related fields. J. Struct. Biol. 116, 190–199 (1996)

  26. 26.

    et al. Structures of the bacterial ribosome at 3.5 Å resolution. Science 310, 827–834 (2005)

  27. 27.

    , & Situs: A package for docking crystal structures into low-resolution maps from electron microscopy. J. Struct. Biol. 125, 185–195 (1999)

  28. 28.

    , , & Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A A47, 110–119 (1991)

  29. 29.

    et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004)

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This work was supported by grants from the VolkswagenStiftung and the Deutsche Forschungsgemeinschaft SFB594 (to R.B.) and SFB638 (to I.S.) and by the European Union and Senatsverwaltung für Wissenschaft, Forschung und Kultur Berlin (UltraStructureNetwork).

Author information

Author notes

    • Mario Halic
    •  & Michael Blau

    These authors contributed equally to this work.


  1. Gene Center, Department of Chemistry and Biochemistry, University of Munich, Feodor-Lynen-Strasse 25, 81377 Munich, Germany

    • Mario Halic
    • , Michael Blau
    • , Thomas Becker
    •  & Roland Beckmann
  2. UltraStructureNetwork, USN, Max Planck Institute for Molecular Genetics, Ihnestrasse 63–73, 14195 Berlin, Germany

    • Thorsten Mielke
    •  & Roland Beckmann
  3. Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK

    • Martin R. Pool
  4. Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany

    • Klemens Wild
    •  & Irmgard Sinning


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Competing interests

Coordinates of the atomic models of SRP have been deposited in the PDB under accession numbers 2j28 and 2j37. The cryo-electron microscopic maps have been deposited in the 3D-EM database under accession numbers EMD1261 (E. coli SRP–RNC), EMD1263 (E. coli RNC) and EMD1264 (mammalian SRP-RNC). Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Roland Beckmann.

Supplementary information

Word documents

  1. 1.

    Supplementary Methods

    Methods section describing programming, purification and reconstitution of ribosomal complexes, followed by description of structure determination by cryo-EM and single particle analysis. This file also contains Supplementary Table 1.

  2. 2.

    Supplementary Figure Legend

    Text to accompany Supplementary Figure 1. Sequence and secondary structure prediction of C-terminal domain of mammalian (Canis familiaris) SRP54

Image files

  1. 1.

    Supplementary Figure 1

    Alignment of the C-terminus of the mammalian SRP54 M domain with secondary structure prediction and usage in model.

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