Abstract
Non-LTR retrotransposons are mobile genetic elements and play a major role in eukaryotic genome evolution and disease. Similar to retroviruses they encode a reverse transcriptase, but their genomic integration mechanism is fundamentally different, and they lack homologs of the retroviral nucleocapsid-forming protein Gag. Instead, their first open reading frames encode distinct multi-domain proteins (ORF1ps) presumed to package the retrotransposon-encoded RNA into ribonucleoprotein particles (RNPs). The mechanistic roles of ORF1ps are poorly understood, particularly of ORF1ps that appear to harbor an enzymatic function in the form of an SGNH-type lipolytic acetylesterase. We determined the crystal structures of the coiled coil and esterase domains of the ORF1p from the Danio rerio ZfL2-1 element. We demonstrate a dimerization of the coiled coil and a hydrolytic activity of the esterase. Furthermore, the esterase binds negatively charged phospholipids and liposomes, but not oligo-(A) RNA. Unexpectedly, the esterase can split into two dynamic half-domains, suited to engulf long fatty acid substrates extending from the active site. These properties indicate a role for lipids and membranes in non-LTR retrotransposition. We speculate that Gag-like membrane targeting properties of ORF1ps could play a role in RNP assembly and in membrane-dependent transport or localization processes.
Highlights
Non-LTR retrotransposons represent a major evolutionary force acting on the structure and composition of eukaryotic genomes [1,2,3,4,5]
We speculate that Gag-like membrane targeting properties of ORF1ps could play a role in ribonucleoprotein particles (RNPs) assembly and in membrane-dependent transport or localization processes
The first structure is that of an N-terminal coiled coil domain that we show to cause a dimerization of the molecule, an assembly mode that is clearly distinct from the trimers formed by the LINE-1 ORF1p [21,22]
Summary
Non-LTR retrotransposons (retrotransposons like the human LINE-1 element that do not contain long terminal repeats, LTRs) represent a major evolutionary force acting on the structure and composition of eukaryotic genomes [1,2,3,4,5]. Despite their significance for evolution and disease, non-LTR retrotransposons are poorly understood on a mechanistic level, especially if compared with LTR retrotransposons and retroviruses [5,6,7]. Non-LTR retrotransposons lack homologs of the Gag protein and do not seem to have viral relatives that would allow a horizontal transfer across cell boundaries [5,6,7]
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