The nuclear RNA exosome. (A) Structure of a complex consisting of the nine-subunit exosome core, Rrp6, Dis3, Rrp47 and single-stranded RNA87 (PDB 5C0W). In this structure, RNA directly accesses Dis3. (B) Structure of a complex consisting of the nine-subunit core, Dis3, a fragment of Rrp6 and RNA consisting of a 5’ stem-loop and a 31 nt single-stranded overhang88 (PDB 4IFD). In this structure, RNA accesses Dis3 via the channel. The RNA within the channel was not fully visualized88. (C) Structure of a complex consisting of the nine-subunit core, Dis3, Rrp6, the exosome-binding domain of MPP6 and an RNA engineered to have two 3’ ends. One 3’ end enters the Rrp6 active site, while the other uses the direct access path to the Dis3 exoribonuclease89 (PDB 5VZJ). (D-F) Cartoons of RNA paths to the exosome, configured similarly to the view in Figure 2A, left panel. (D) Path by which a structured RNA substrate can directly access the Dis3 exoribonuclease. (E) Path by which an RNA substrate passes through the central channel to reach the Dis3 exoribonuclease. The conformation of Dis3 differs between the direct access and channel-dependent paths42,88,90–92. (F) RNA path to Rrp6.