Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses
Fig 7
Schematic illustration of structural plasticity in Vprmus-modified CRL4DCAF1-CtD, and implications for ubiquitin transfer.
(A) Rotation of the CRL4 stalk increases the space accessible to catalytic elements at the distal tip of the stalk, forming a ubiquitylation zone around the core. (B) Flexible tethering of SAMHD1 to the core by Vprmus places the bulk of SAMHD1 in the ubiquitylation zone and optimises surface accessibility. Under the experimental conditions, SAMHD1 adopts a monomer-dimer equilibrium, with both forms being competent for Vpr-binding. In B-C, only monomeric SAMHD1 is schematically indicated for clarity. (C) Modification of CUL4-WHB with NEDD8, triggered by substrate binding, leads to increased mobility of these distal stalk elements (CUL4-WHB, ROC1 RING domain) [56], further extending the ubiquitylation zone and activating the formation of a catalytic assembly for ubiquitin transfer (see also D) [72]. (D) Dynamic processes A-C together create numerous possibilities for assembly of the catalytic machinery (CUL4-NEDD8 WHB, ROC1, ubiquitin-(ubi-)charged E2) on surface-exposed SAMHD1 lysine side chains. Here, three of these possibilities are exemplified schematically. In this way, ubiquitin coverage on SAMHD1 is maximised.