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Dimerization regulates both deaminase-dependent and deaminase-independent HIV-1 restriction by APOBEC3G.

Dimerization regulates both deaminase-dependent and deaminase-independent HIV-1 restriction by APOBEC3G.
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Morse M, Huo R, Feng Y, Rouzina I, Chelico L, Williams MC,


Morse M, Huo R, Feng Y, Rouzina I, Chelico L, Williams MC, (click to view)

Morse M, Huo R, Feng Y, Rouzina I, Chelico L, Williams MC,

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Nature communications 2017 09 198(1) 597 doi 10.1038/s41467-017-00501-y

Abstract

APOBEC3G (A3G) is a human enzyme that inhibits human immunodeficiency virus type 1 (HIV-1) infectivity, in the absence of the viral infectivity factor Vif, through deoxycytidine deamination and a deamination-independent mechanism. A3G converts from a fast to a slow binding state through oligomerization, which suggests that large A3G oligomers could block HIV-1 reverse transcriptase-mediated DNA synthesis, thereby inhibiting HIV-1 replication. However, it is unclear how the small number of A3G molecules found in the virus could form large oligomers. Here we measure the single-stranded DNA binding and oligomerization kinetics of wild-type and oligomerization-deficient A3G, and find that A3G first transiently binds DNA as a monomer. Subsequently, A3G forms N-terminal domain-mediated dimers, whose dissociation from DNA is reduced and their deaminase activity inhibited. Overall, our results suggest that the A3G molecules packaged in the virion first deaminate viral DNA as monomers before dimerizing to form multiple enzymatically deficient roadblocks that may inhibit reverse transcription.APOBEC3G inhibits HIV-1 viral replication via catalytic and non-catalytic processes. Here the authors show that APOBEC3G binds single-stranded DNA as an active deaminase monomer, subsequently forming catalytic-inactive dimers that block reverse transcriptase-mediated DNA synthesis.

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