The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization

Bohn, Markus-Frederik; Shandilya, Shivender M.D.; Silvas, Tania V.; Nalivaika, E.A.; Kouno, Takahide; Kelch, Brian A.; Ryder, Seán; KurtYilmaz, N.; Somasundaran, Mohan; Schiffer, Celia A.

doi:10.1016/j.str.2015.03.016

Cited by 84 publications

(149 citation statements)

References 75 publications

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“…4, B and C). This improved activity relative to the A3Bctd-QM⌬loop3 parental construct is consistent with the more open active site conformation reported recently for A3A (34,40) (Fig. 3E).…”

Section: Resultssupporting

confidence: 92%

“…As observed for the closely related Z1-type deaminase domains A3A and A3Gctd, ␤2 on the exposed edge of the ␤-sheet is interrupted by a short 3 10 helical segment (helix 1 in Fig. 2A; A3A (34,40); A3Gctd (30,31,33,37,39)). Correspondingly, the C-terminal end of ␣2, which interacts with this helical segment, is bent toward the discontinuous ␤2 (Fig.…”

Section: Resultsmentioning

confidence: 62%

“…Three of these substitutions (F200S, W228S, and L230K) changed A3Bctd residues to the corresponding sequence of the homologous A3A protein, which recently yielded to structural studies (34,40). F308K mimics the F302K and F310K substitutions used in structural studies of A3Fctd and A3Gctd, respectively (29 -31, 33).…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain

Shi

Carpenter

Kurahashi

et al. 2015

Journal of Biological Chemistry

183

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Background: APOBEC3B-catalyzed DNA cytosine deamination causes mutations in cancer. Results: We present the first APOBEC3B catalytic domain crystal structures including a dCMP-bound form. Conclusion: A closed active site conformation distinguishes APOBEC3B from related enzymes and suggests that conformational changes are central to the overall single-stranded DNA binding mechanism. Significance: These high resolution structures provide a foundation for inhibitor development.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 62%

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Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain

Shi

Carpenter

Kurahashi

et al. 2015

Journal of Biological Chemistry

183

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“…Although the crystal structure study of A3A suggested a cooperative dimerization model for its action on DNA, the structural basis of A3A's RNA-editing and RNP complexforming abilities is still unknown (37,59).…”

Section: Discussionmentioning

confidence: 99%

“…Biochemical studies and atomic force microscopy observations showed that APOBEC3G (A3G) formed a dimer (34,35) or an oligomer (36). APOBEC3A (A3A) was very recently crystalized as a dimer (37). Also, the dimeric structure of APOBEC1 (A1) was suggested by biochemical studies (13,38,39).…”

Section: Detection Of Apobec Homodimer Formation By the Monomeric Kusmentioning

confidence: 99%

Functional requirements of AID’s higher order structures and their interaction with RNA-binding proteins

Mondal

Begum

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. Although both the N and C termini of AID have unique functions in DNA cleavage and recombination, respectively, during SHM and CSR, their molecular mechanisms are poorly understood. Using a bimolecular fluorescence complementation (BiFC) assay combined with glycerol gradient fractionation, we revealed that the AID C terminus is required for a stable dimer formation. Furthermore, AID monomers and dimers form complexes with distinct heterogeneous nuclear ribonucleoproteins (hnRNPs). AID monomers associate with DNA cleavage cofactor hnRNP K whereas AID dimers associate with recombination cofactors hnRNP L, hnRNP U, and Serpine mRNA-binding protein 1. All of these AID/ribonucleoprotein associations are RNA-dependent. We propose that AID's structurespecific cofactor complex formations differentially contribute to its DNA-cleavage and recombination functions., which is expressed in antigen-stimulated mature B cells, is essential for Ig somatic hypermutation (SHM) and class-switch recombination (CSR) (1, 2). AID induces DNA breaks at the variable (V) and switch (S) regions during SHM and CSR, respectively (3, 4). Although both processes are initiated by AID-induced DNA cleavage, point mutations at the V region are executed mostly by error-prone DNA repair whereas CSR is accomplished by recombination of cleaved ends at donor and acceptor S regions (5, 6). However, the detailed mechanisms by which AID carries out the two mechanistically distinct functions for SHM and CSR have yet to be uncovered (7). Studies on AID mutants revealed that AID's N-and C-terminal domains are distinctly required for its DNA-cleavage and recombination functions, respectively (8-10). Mutations at the N terminus of AID impair SHM as well as CSR whereas those at the C terminus abrogate CSR only and show increased SHM activity. Recent studies demonstrated that the CSR process after DNA cleavage, including the synapsis formation between cleaved ends, is impaired with the C-terminally defective AID, indicating that AID's C terminus confers a CSR-specific recombination function, independent of AID's DNA cleavage function, by an unknown mechanism (11,12).AID belongs to the APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide) family of cytidine deaminases (CDDs) and shows high sequence homology with APOBEC1 (A1) (1,13,14), which edits apolipoprotein B (APOB) mRNA. The APOB mRNA editing ability of A1 is highly dependent on its cofactors, A1CF/ACF (15, 16) and RBM47 (17), both of which belong to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. Recently, two A1CF-like hnRNPs, hnRNP K and hnRNP L, were identified as the cofactors of AID and found to be involved in the cleavage and recombination of DNA, respectively (18). Because the N and C termini of AID differentially regulate two functions of AID-cleavage and recombination, respectivelywe speculated that the AID termini would be critical...

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ISG20: an enigmatic antiviral RNase targeting multiple viruses

et al. 2022

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Interferon‐stimulated gene 20 kDa protein (ISG20) is a relatively understudied antiviral protein capable of inhibiting a broad spectrum of viruses. ISG20 exhibits strong RNase properties, and it belongs to the large family of DEDD exonucleases, present in both prokaryotes and eukaryotes. ISG20 was initially characterized as having strong RNase activity in vitro, suggesting that its inhibitory effects are mediated via direct degradation of viral RNAs. This mechanism of action has since been further elucidated and additional antiviral activities of ISG20 highlighted, including direct degradation of deaminated viral DNA and translational inhibition of viral RNA and nonself RNAs. This review focuses on the current understanding of the main molecular mechanisms of viral inhibition by ISG20 and discusses the latest developments on the features that govern specificity or resistance to its action.

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The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization

Cited by 84 publications

References 75 publications

Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain

Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain

Functional requirements of AID’s higher order structures and their interaction with RNA-binding proteins

ISG20: an enigmatic antiviral RNase targeting multiple viruses

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