Human LINE-1 retrotransposition requires a metastable coiled coil and a positively charged N-terminus in L1ORF1p

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Abstract

LINE-1 (L1) is an autonomous retrotransposon, which acted throughout mammalian evolution and keeps contributing to human genotypic diversity, genetic disease and cancer. L1 encodes two essential proteins: L1ORF1p, a unique RNA-binding protein, and L1ORF2p, an endonuclease and reverse transcriptase. L1ORF1p contains an essential, but rapidly evolving N-terminal portion, homo-trimerizes via a coiled coil and packages L1RNA into large assemblies. Here, we determined crystal structures of the entire coiled coil domain of human L1ORF1p. We show that retrotransposition requires a non-ideal and metastable coiled coil structure, and a strongly basic L1ORF1p amino terminus. Human L1ORF1p therefore emerges as a highly calibrated molecular machine, sensitive to mutation but functional in different hosts. Our analysis rationalizes the locally rapid L1ORF1p sequence evolution and reveals striking mechanistic parallels to coiled coil-containing membrane fusion proteins. It also suggests how trimeric L1ORF1p could form larger meshworks and indicates critical novel steps in L1 retrotransposition.

Data availability

The following data sets were generated

1. Khazina E
2. Weichenrieder O
(2018) Structure of the human LINE-1 ORF1p coiled coil domain
Protein Data Bank 6FIA.

https://www.rcsb.org/

Article and author information

Author details

Elena Khazina

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

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-3626-4422
Oliver Weichenrieder

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

For correspondence
oliver.weichenrieder@tuebingen.mpg.de

Competing interests
Oliver Weichenrieder, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-5818-6248

Funding

Max-Planck-Gesellschaft (Open-access funding)

Oliver Weichenrieder

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.