Abstract
APOBEC3G (A3G) is a potent restriction factor of HIV-1. The N-terminal domain of A3G (A3G-CD1) is responsible for oligomerization and nucleic acid binding, both of which are essential for anti-HIV activity. As a countermeasure, HIV-1 viral infectivity factor (Vif) binds A3G-CD1 to mediate A3G degradation. The structural basis for the functions of A3G-CD1 remains elusive. Here, we report the crystal structures of a primate A3G-CD1 (rA3G-CD1) alone and in complex with single-stranded DNA (ssDNA). rA3G-CD1 shares a conserved core structure with the previously determined catalytic APOBECs, but displays unique features for surface charge, dimerization and nucleic acid binding. Its co-crystal structure with ssDNA reveals how the conformations of loops and residues surrounding the Zn-coordinated centre (Zn-centre) change upon DNA binding. The dimerization interface of rA3G-CD1 is important for oligomerization, nucleic acid binding and Vif-mediated degradation. These findings elucidate the molecular basis of antiviral mechanism and HIV-Vif targeting of A3G.
Highlights
APOBEC3G (A3G) is a potent restriction factor of HIV-1
Since the CD1 of human A3G has poor solubility in Escherichia coli, we examined the expression and solubility of multiple A3G homologues from primates, and found that rA3G-CD1 is more soluble than hA3G-CD1
A single K128D mutation enables rA3G to be targeted by HIV-1 viral infectivity factor (Vif) for proteasomal degradation[29] (Fig. 5a, left panel), confirming that hA3G-CD1 and rA3G-CD1 likely share conserved Vif–A3G interface interactions with the exception of D/K128
Summary
The N-terminal domain of A3G (A3G-CD1) is responsible for oligomerization and nucleic acid binding, both of which are essential for anti-HIV activity. The dimerization interface of rA3G-CD1 is important for oligomerization, nucleic acid binding and Vif-mediated degradation. These findings elucidate the molecular basis of antiviral mechanism and HIV-Vif targeting of A3G. Correspondence and requests for materials should be addressed to APOBEC3s (A3s) are deoxycytidine deaminases that have important roles in mammalian innate immune responses Members of this family catalyze the conversion of cytosine into uracil on single-stranded DNA (ssDNA) and restrict retroviral replication and endogenous retroelements. A recently reported NMR structure of a human A3G-CD1 variant (A3G-sNTD) overcame the solubility issue by mutating 20% of the residues, yielding a mutant variant that no longer oligomerizes, interacts with RNA, nor gets degraded by Vif[32]. The high-resolution structure of a fully-functional CD1 is still unresolved
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