<p>(A) A diagram of the 225 kDa <i>S. cerevisiae</i> Ubr1. The indicated evolutionarily conserved regions of Ubr1 are the UBR box, the BRR (basic residues-rich) domain, the Cys/His-rich RING-H2 domain, and the AI (<u>a</u>uto<u>in</u>hibitory) domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Tasaki1" target="_blank">[18]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Xie1" target="_blank">[30]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Hwang3" target="_blank">[33]</a>. Three missense mutations in patients #1-3 of the present work are indicated as well (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B, C</a>). (B) Ribbon diagram of the <i>S. cerevisiae</i> UBR domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Choi1" target="_blank">[48]</a> in a complex with RLGES, the N-terminal region of the separase-produced fragment of Scc1, a subunit of cohesin <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Rao1" target="_blank">[75]</a>. The bound RLGES peptide is shown as a stick model, with carbon atoms colored yellow. Several residues are marked with a black sphere and numbered to facilitate the tracing of the polypeptide chain. The names of residues of the RLGES peptide are in red, with the letter ‘s’ (substrate) appended to their position numbers. Side-chains of residues in the UBR domain that are present near JBS mutations (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B, C</a>) are shown in a stick form, with carbon atoms colored green. Three coordinated zinc ions of the UBR domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Choi1" target="_blank">[48]</a> are shown as red spheres. (C) Close-up view of the UBR region near the V146L mutation (patient #1; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B</a>). In panel B, this region of UBR is boxed and labeled as ‘C’. The residues of UBR that accommodate the position-2 Leu residue (‘Leu2s’) of the RLGES peptide substrate are shown and labeled. The van der Waals sphere of the mutant Leu residue, in the UBR1<sup>V146L</sup> mutant, is shown as purple dots. (D) Close-up view of the UBR region near the H160R mutation (patient #2, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B</a>). In panel B, this region of UBR is boxed and labeled as ‘D’. The residues of UBR coordinating Zn3 atom are shown and labeled. The van der Waals sphere of the mutant Arg residue, in the UBR1<sup>H160R</sup> mutant, is shown as purple dots. The views in (C) and (D) are oriented to maximize visibility of mutation-proximal residues.</p
