(A) Distinct types of protein architecture among ORF1 proteins from non-LTR retrotransposons. Top: General organization of an RNA from a non-LTR retrotransposon, encoding a first, accessory ORF1 and a second, catalytic ORF2 that harbors both endonuclease (EN) and reverse transcriptase (RT) functions required for target-primed reverse transcription. Bottom: Commonly found types of ORF1p architecture, represented by the human L1 element (see Figure 1A for details), the Drosophila melanogaster Jockey element, and the Danio rerio ZfL2-1 element. All three proteins harbor coiled coil sequences with heptads colored in grey and black. Furthermore, all three proteins contain RNA binding elements: In the human L1ORF1p, a distinct RRM domain cooperates with a C-terminal domain (CTD) and the coiled coil. In Jockey-like ORF1ps, single or tandem RRMs are followed by one or more Gag-like CCHC zinc knuckles, and the ZfL2-1 ORF1p contains an arginine-rich motif (ARM). Finally, the ZfL2-1 ORF1p hosts a lipid binding SGNH esterase domain (ES) (Schneider et al., 2013). (B) Variability in mammalian L1ORF1p sequences. Bar diagrams are aligned via the C-terminal end of the coiled coil domain. Only the conserved portions of the L1ORF1ps can be unambiguously aligned (Boissinot and Sookdeo, 2016; Khazina et al., 2011; Yang et al., 2014). The non-conserved part of the coiled coil harbors a variable number of heptad repeats (magenta for non-heptad interruptions). The NTRs are of different length, but all show an accumulation of positive charges at the N-terminus (blue). Phosphorylation sites identified in the human NTR are marked in yellow (Cook et al., 2015). See Supplemental file 1 for the individual sequences. (C) Coiled coil heptad expansion and deletion in murine L1 elements. In the mouse, active L1 elements belong to different lineages (A1, Tf1, Gf1), where the non-conserved part of the L1ORF1p coiled coil has undergone heptad duplications and deletions (Sookdeo et al., 2013). Furthermore, murine L1ORF1ps contain a stutter as opposed to the stammer in human L1ORF1p, but the precise alignment of murine and human sequences remains ambiguous in the non-conserved part of the sequence. L1_Tf1 is also known as L1spa (Kingsmore et al., 1994; Naas et al., 1998). See Supplemental file 1 for the individual sequences.