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Trimeric structure and flexibility of the L1ORF1 protein in human L1 retrotransposition

Nature Structural & Molecular Biology volume 18, pages 10061014 (2011) | Download Citation


The LINE-1 (L1) retrotransposon emerges as a major source of human interindividual genetic variation, with important implications for evolution and disease. L1 retrotransposition is poorly understood at the molecular level, and the mechanistic details and evolutionary origin of the L1-encoded L1ORF1 protein (L1ORF1p) are particularly obscure. Here three crystal structures of trimeric L1ORF1p and NMR solution structures of individual domains reveal a sophisticated and highly structured, yet remarkably flexible, RNA-packaging protein. It trimerizes via an N-terminal, ion-containing coiled coil that serves as scaffold for the flexible attachment of the central RRM and the C-terminal CTD domains. The structures explain the specificity for single-stranded RNA substrates, and a mutational analysis indicates that the precise control of domain flexibility is critical for retrotransposition. Although the evolutionary origin of L1ORF1p remains unclear, our data reveal previously undetected structural and functional parallels to viral proteins.

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We thank the staff at the Swiss Light Source (Villigen, Switzerland) for assistance during data collection, M.D. Hartmann for assistance with structure analysis and T. Holder for the movie script. Furthermore, we thank M. Fauser for an introduction to eukaryotic cell culture. We are grateful to E. Izaurralde for continued support and discussion. E.K. and O.W. were supported by a personal VIDI grant (NWO-CW 700.54.427) to O.W. from the Dutch National Science Organization (NWO).

Author information


  1. Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.

    • Elena Khazina
    • , Vincent Truffault
    • , Regina Büttner
    • , Steffen Schmidt
    •  & Oliver Weichenrieder
  2. Department of Protein Evolution, Max Planck Institute for Developmental Biology, Tübingen, Germany.

    • Murray Coles


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E.K. is the leading author, designed, performed and analyzed experiments, established cell culture, determined the crystal structures and wrote the manuscript. V.T. and M.C. recorded and analyzed NMR spectra, determined and analyzed NMR structures, and contributed to the manuscript. R.B. established cell culture, and performed and analyzed experiments. S.S. analyzed data and contributed to the manuscript. O.W. designed research, analyzed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Oliver Weichenrieder.

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    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Methods


  1. 1.

    Supplementary Movie 1

    Flexibility and domain movements in the L1ORF1p trimer. While rotating once around the pseudo–three-fold axis of the trimer, the movie smoothly interpolates between the structural conformations observed in the three crystal forms (cfI, cfII and cfIII). Morphing transitions are from cfI via cfII to cfII and directly back to cfI. This is repeated once. The coiled coil is colored in gray, the RRM domains are in red and the CTD domains are in blue. Interdomain linkers are in lime and the central chloride ions are shown as yellow spheres.

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