Volume 36, Issue 6, Pages (December 2009)

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Volume 36, Issue 6, Pages 1095-1102 (December 2009) Insights into Ubiquitin Transfer Cascades from a Structure of a UbcH5B∼Ubiquitin- HECTNEDD4L Complex Hari B. Kamadurai, Judith Souphron, Daniel C. Scott, David M. Duda, Darcie J. Miller, Daniel Stringer, Robert C. Piper, Brenda A. Schulman Molecular Cell Volume 36, Issue 6, Pages 1095-1102 (December 2009) DOI: 10.1016/j.molcel.2009.11.010 Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 1 Structure of UbcH5B∼Ub-HECTNEDD4L (A–C) Three views, separated by 90° in y (B) and then 60° in x (C) of UbcH5B (cyan)∼Ub (yellow)-HECTNEDD4L (magenta). Catalytic residues (here serines, but normally cysteines, as indicated) are green spheres. (D–F) Structures of HECTSMURF2 (violet) (D), UbcH7-HECTE6AP (navy, pink) (E), and HECTWWP1 (maroon) (F), oriented as UbcH5B∼Ub-HECTNEDD4L N lobe in (B). Catalytic cysteines are green spheres. Molecular Cell 2009 36, 1095-1102DOI: (10.1016/j.molcel.2009.11.010) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 2 UbcH5B-HECTNEDD4L N Lobe Interactions (A) Structural superposition of the E2s in UbcH5B (cyan)∼Ub (not shown for clarity)-HECTNEDD4L (magenta) and UbcH7-HECTE6AP (navy, pink). Catalytic residues are green spheres. (B) Autoradiogram showing time course of pulse-chase transfer of [32P]Ub from UbcH5B (E2∼Ub) to WT and the Y736A mutant HECTNEDD4L (E3∼Ub). (C) Close up view of interactions between UbcH5B (cyan, black labels) and HECTNEDD4L N lobe (magenta), oriented by 90° rotation in y relative to (A). (D) Close up view of interactions between UbcH7 (navy) and HECTE6AP (salmon), in same orientation as UbcH5B-HECTNEDD4L in (C). Oxygens are red, nitrogens blue, and salt-bridges/H-bonds dashes. Molecular Cell 2009 36, 1095-1102DOI: (10.1016/j.molcel.2009.11.010) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 3 Ub-HECTNEDD4L C Lobe Interface (A) Close up view of Ub (yellow)-HECTNEDD4L (magenta). In the structure, the active site cysteines are substituted with serines, but are labeled C85∗ and C922∗ from UbcH5B and NEDD4L, respectively, to indicate native sequences. Oxygens are red, nitrogens blue, and salt bridges/H-bonds dashes. (B and C) Autoradiograms showing time course of pulse-chase transfer of [32P]Ub from UbcH5B (E2∼Ub) to GST-tagged HECT domain of NEDD4L (E3∼Ub), for WT and the indicated mutant of NEDD4L (B) or Ub (C). Molecular Cell 2009 36, 1095-1102DOI: (10.1016/j.molcel.2009.11.010) Copyright © 2009 Elsevier Inc. Terms and Conditions

Figure 4 Model for E2-to-HECT E3 Transthiolation (A) Structural model of UbcH5B (cyan, catalytic Cys85 green)∼Ub (yellow)-NEDD4L HECT domain (magenta) in a putative conformation for the transthiolation reaction. ∼4° rotation about the N and C lobes allows NEDD4L catalytic Cys922 (green) to approach the Ub C terminus. Intermolecular contact residues poised to influence transthiolation are represented as sticks. (B) Conservation among HECTs displayed on HECTNEDD4L surface (white, no conservation; magenta, 100% identity except catalytic cysteine that is green), in model of transthiolation complex with UbcH5B∼Ub. (C) Autoradiograms showing time course of pulse-chase transfer of [32P]Ub from UbcH5B (E2∼Ub) to GST-tagged HECT domain of NEDD4L (E3∼Ub) for WT and indicated mutants in UbcH5B (top) or NEDD4L (bottom). Molecular Cell 2009 36, 1095-1102DOI: (10.1016/j.molcel.2009.11.010) Copyright © 2009 Elsevier Inc. Terms and Conditions