Drosophila CG3303 is an essential endoribonuclease linked to TDP-43-mediated neurodegeneration

Laneve, Pietro; Piacentini, Lucia; Casale, Assunta Maria; Capauto, Davide; Gioia, Ubaldo; Cappucci, Ugo; Di Carlo, Valerio; Bozzoni, Irene; Di Micco, Patrizio; Morea, Veronica; Di Franco, Carmela Antonia; Caffarelli, Elisa

Comparison of Drosophila and XendoU protein sequences showed significant differences in length (592 amino acids for CG2145 and 322 residues for CG3303), which are mostly contributed by the N-terminal regions (Fig. 1a) . The C-terminal regions, instead, have similar length (281 and 276 amino acids, respectively) and high sequence identity (41%). The multiple sequence alignment of CG3303 and CG2145 with XendoU and human PP11 homologues, shown in Fig. 1b , highlighted that the 1-250 region of XendoU, comprising most of the residues previously reported to be involved in catalytic activity 2 , was well conserved in both Drosophila isoforms and PP11. Conversely, the 251-292 region is more variable in both length and sequence. This region contains several residues, including N270, H272, G277, T278 and Y280, involved in binding the RNA substrate based on the experimentally determined XendoU structure 3 . The high sequence variability in this region indicates that the mode of RNA substrate binding is likely to be different between the two Drosophila proteins.