Modeling pathogenic amino acid substitutions in Human EXOSC2 and S. cerevisiae Rrp4. (A) Structural modeling of the human EXOSC2 p.Gly30Val (G30V) amino acid substitution identified in patients with SHRF syndrome in the human RNA exosome. Zoomed-in representations of the interface between EXOSC2 (teal blue) and EXOSC4 (light gray) modeling the native EXOSC2 Gly30 (G30) residue (left) or the pathogenic EXOSC2 Val30 (V30) residue (right) are depicted. The EXOSC2 Gly30 residue is located in the amino-terminal domain of EXOSC2, near the interface of EXOSC2 with the core subunit, EXOSC4. (B) Structural modeling of budding yeast Rrp4 Gly58Val (G58V) amino acid change, corresponding to EXOSC2 p.Gly30Val amino acid change, in the budding yeast exosome. Zoomed-in representations of the interface between Rrp4 (teal blue) and the budding yeast EXOSC4 ortholog, Rrp41 (light gray), modeling the native Rrp4 Gly58 (G58) residue (left) or the modeled pathogenic Rrp4 Val58 (V58) residue (right) are shown. The Rrp4 Gly58 residue is conserved between human and yeast and, similarly to EXOSC2 Gly30, is located in the amino-terminal domain of Rrp4, near the interface of Rrp4 with the core subunit, Rrp41. (C) Structural modeling of the EXOSC2 p.Gly198Asp (G198D) amino acid substitution identified in patients with SHRF syndrome in the human RNA exosome. Zoomed-in representations of EXOSC2 modeling the native EXOSC2 Gly198 (G198) residue (left) or the pathogenic EXOSC2 Asp198 (D198) residue (right) are shown. The EXOSC2 Gly198 residue is located in the KH-domain of EXOSC2 within a dense region of the protein, surrounded by four β-sheets. (D) Structural modeling of the budding yeast Rrp4 Gly226Asp (G226D) amino acid change, corresponding to the EXOSC2 p.Gly198Asp amino acid change, in the budding yeast RNA exosome. Zoomed-in representations of Rrp4 modeling the native Rrp4 Gly226 (G226) residue (left) or the modeled pathogenic Rrp4 Asp226 (D226) residue (right) are shown. The Rrp4 Gly226 residue, which is conserved between human and yeast, is located in the KH-domain of Rrp4 within a dense region of the protein, surrounded by four β-sheets. Structural modeling in A and C was performed with the human RNA exosome structure (PDB 6D6R) (Weick et al. 2018) and in B and D with the yeast RNA exosome structure (PDB 6FSZ) (Schuller et al. 2018) using PyMOL (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC).
