Crystal structure of human Acinus RNA recognition motif domain

Abstract

Acinus is an abundant nuclear protein involved in apoptosis and splicing. It has been implicated in inducing apoptotic chromatin condensation and DNA fragmentation during programmed cell death. Acinus undergoes activation by proteolytic cleavage that produces a truncated p17 form that comprises only the RNA recognition motif (RRM) domain. We have determined the crystal structure of the human Acinus RRM domain (AcRRM) at 1.65 Å resolution. It shows a classical four-stranded antiparallel β-sheet fold with two flanking α-helices and an additional, non-classical α-helix at the C-terminus, which harbors the caspase-3 target sequence that is cleaved during Acinus activation. In the structure, the C-terminal α-helix partially occludes the potential ligand binding surface of the β-sheet and hypothetically shields it from non-sequence specific interactions with RNA. Based on the comparison with other RRM-RNA complex structures, it is likely that the C-terminal α-helix changes its conformation with respect to the RRM core in order to enable RNA binding by Acinus.

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“…In addition to this known part of the ASAP complex in animals, the AlphaFold model revealed a potential additional interaction between the RRM domain of ACINUS (residues 445 to 541) and the ubiquitin-like domain of SAP18. The interface, which covers an area of 588Å 2 , involved residues from the L1, L3 and L5 loops (Supplementary Figure 7D), the first two being the most conserved regions on the surface of the domain according to Fernandes and colleagues (Fernandes et al, 2018). With only two salt bridges and some hydrophobic interactions, the interaction between the two partners was not strong according to the PISA server (Krissinel and Henrick, 2007) and could potentially be strengthened upon interactions with other partners including RNA.…”