Hijacking through mimicry

Viruses use a variety of strategies to evade and/or neutralize host defense systems. In the case of HIV and other lentiviruses, the viral protein Vif has a key role in neutralizing the host restriction factor APOBEC3G, which functions to inhibit viral replication. Vif interaction results in targeted degradation of APOBEC3G through recruitment of an E3 ubiquitin ligase complex formed by CUL5 and the substrate adaptors ELOB and ELOC, in addition to the host protein CBF-β. To shed light on the precise mechanism by which Vif hijacks host factors to neutralize innate defenses, Huang and colleagues have solved the crystal structure of a pentameric HIV Vif–CBF-β–CUL5–ELOB–ELOC complex. Vif forms a new fold composed of two domains, separated by a zinc-binding site, that bear resemblance to the cellular proteins SOCS2 and VHL, both substrate-binding proteins known to interact with ELOBC. The complex, organized through interactions with Vif, assumes a U shape with CUL5 forming one arm and Vif–CBF-β the other, while ELOC interacts with both Vif and CUL5 to form the curve of the U. ELOB makes contact with only ELOC. Structural comparison shows that Vif and SOCS2, despite limited sequence homology, use the same interface to bind ELOC. The known preference of Vif for binding CUL5 over the related E3 ligase CUL2 could be accounted for by specific residues within CUL5 that are not conserved in CUL2. Those same residues were also previously shown to mediate the specific interaction of CUL5 with SOCS2, thus further supporting the idea that Vif acts as a SOCS2 mimic to hijack cellular proteins. In addition to revealing the structural basis for Vif activity, the structure may prove useful in the design of anti-HIV drugs. (Nature 505, 229–233, 2014)


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Larochelle, S. Hijacking through mimicry. Nat Struct Mol Biol 21, 117 (2014). https://doi.org/10.1038/nsmb.2774

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