To Process or to Decay: A Mechanistic View of the Nuclear RNA Exosome

Architecture of the nuclear exosome holocomplex: Exo14n. (A) Composite structure of eukaryotic Exo13n (cartoon representation) in resting mode and in distributive degradation mode (e.g., Rrp6-mediated). The model is a superposition of several crystal structures: Exo10–Rrp6–Rrp47 (Makino et al. 2015), Exo9-Mpp6_M (Falk et al. 2017a; Wasmuth et al. 2017), Rrp6–Rrp47–Mtr4_N (Schuch et al. 2014), and the Rrp6-RNA exosome complex (Wasmuth et al. 2014). The helicase core of Mtr4 (Jackson et al. 2010; Weir et al. 2010) is shown in a hypothetical arrangement, linked to the Exo13n core by the interaction of the DExH core with Mpp6_N (Schuller et al. 2018; Weick et al. 2018) and by the interaction of Mtr4_N with the Rrp6_N–Rrp47_N heterodimerization module (Schuch et al. 2014). N stands for amino-terminal domain; M for middle domain. The low-complexity carboxy-terminal sequences of Mpp6 and Rrp6 are flexible and not shown. Exo9: the upper ring of the S1/KH proteins is shown in warm colors (Csl4 in yellow, Rrp4 in orange and Rrp40 in salmon) and the lower ring of six RNase-PH like proteins in gray. The processive ribonuclease Rrp44 (light pink) is positioned at the lower ring of Exo9 (here in the open conformation without RNA). The nuclear cofactors Mpp6 (cyan), Rrp6 (red), Rrp47 (purple), and Mtr4 (blue) are at the top of the upper ring. A cartoon model of the nuclear exosome in the resting state/Rrp6 active state, corresponding to the cartoon model in Figure 5, is shown below. (B) Composite structure of eukaryotic Exo14n (cartoon representation) in processive mode (i.e., Rrp44-mediated). The model is based on the cryo-EM structure of a pre-60S-bound complex (Schuller et al. 2018), the crystal structure of RNA-bound Exo10-Rrp6_C (Makino et al. 2013a), and cryo-EM maps of the human Exo14 (Gerlach et al. 2018; Weick et al. 2018). The RNA is threaded through Mtr4 into the exosome central channel and to the Rrp44 ribonuclease (in closed conformation). A cartoon model of the nuclear exosome in the Rrp44 active state, corresponding to the cartoon model in Figure 5, is shown below.