5w45
Crystal structure of APOBEC3H
Structural highlights
FunctionABC3H_HUMAN DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms (PubMed:16571802, PubMed:16920826, PubMed:18779051, PubMed:18827027, PubMed:20062055, PubMed:22915799, PubMed:29290613). The A3H-var/haplotype 2 exhibits antiviral activity against vif-deficient HIV-1 (PubMed:18299330, PubMed:21835787, PubMed:23097438, PubMed:29290613). After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA (PubMed:18299330). The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells (PubMed:18299330). Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA (PubMed:20062055). Exhibits antiviral activity also against T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons (PubMed:20062055, PubMed:22457529).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedAPOBEC3H (A3H) is a member of the APOBEC3 subfamily of DNA cytosine deaminases that are important for innate immune defense and have been implicated in cancer biogenesis. To understand the structural basis for A3H biochemical function, we determined a high-resolution structure of human A3H and performed extensive biochemical analysis. The 2.49 A crystal structure reveals a uniquely long C-terminal helix 6 (h6), a disrupted beta5 strand of the canonical five-stranded beta-sheet core, and a long loop 1 around the Zn-active center. Mutation of a loop 7 residue, W115, disrupted the RNA-mediated dimerization of A3H yielding an RNA-free monomeric form that still possessed nucleic acid binding and deaminase activity. A3H expressed in HEK293T cells showed RNA dependent HMW complex formation and RNase A-dependent deaminase activity. A3H has a highly positively charged surface surrounding the Zn-active center, and multiple positively charged residues within this charged surface play an important role in the RNA-mediated HMW formation and deaminase inhibition. Furthermore, these positively charged residues affect subcellular localization of A3H between the nucleus and cytosol. Finally, we have identified multiple residues of loop 1 and 7 that contribute to the overall deaminase activity and the methylcytosine selectivity. Understanding the Structure, Multimerization, Subcellular Localization and mC Selectivity of a Genomic Mutator and Anti-HIV Factor APOBEC3H.,Ito F, Yang H, Xiao X, Li SX, Wolfe A, Zirkle B, Arutiunian V, Chen XS Sci Rep. 2018 Feb 28;8(1):3763. doi: 10.1038/s41598-018-21955-0. PMID:29491387[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
