Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business

Wedekind, Joseph E.; Dance, Geoffrey S.C.; Sowden, Mark P.; Smith, Harold C.

doi:10.1016/s0168-9525(03)00054-4

Cited by 269 publications

(267 citation statements)

References 71 publications

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“…1B), the noncatalytic C-terminal domain (NCCTD; EcCDA residues 189-294), and the spatial arrangement between domains. Conservation of the subunit interfaces between tetramers and dimers implied that the latter arose through gene duplication of an ancestral monomer that adopted a tetrameric quaternary fold (21,29). This observation accounts for the maintenance of the fundamental ␤-triangle fold in both N-and Cterminal domains of dimeric EcCDA (28).…”

Section: Resultsmentioning

confidence: 98%

“…The subdomain structure ␣2␤3␣3 (Fig. 1B) and signature sequence have been dubbed a zinc-dependent deaminase motif characteristic of C-to-U deaminases of pyrimidine metabolism, as well as C-to-U and A-to-I RNA-editing enzymes (21,34). Key structural differences exist between CDA and ScCD structures that affect substrate specificity.…”

Section: Resultsmentioning

confidence: 99%

“…Misalignment was likely because the N-terminal 48-aa helix bundle from EcCDA does not appear in the structures of either ScCDA, B. subtilis CDA, or ScCD (29,30), and therefore should not be considered part of the core deaminase fold. The need for new APOBEC-1-related protein models is underscored by the fact that the EcCDA-based model has been adopted by other laboratories attempting to elucidate the structure and function of APOBEC-1-related protein family members (36,41), but has been criticized subsequently for lack of structural rigor (21,35).…”

Section: Resultsmentioning

confidence: 99%

“…This idea was intriguing because edited mRNAs either encode novel proteins or lose the ability to express proteins (20,21). Consistent with expression of a novel protein from edited mRNA, de novo protein synthesis was required for CSR subsequent to AID activation (22).…”

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The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

Xie

Sowden

Dance

et al. 2004

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

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Activation-induced deaminase (AID) uses base deamination for class-switch recombination and somatic hypermutation and is related to the mammalian RNA-editing enzyme apolipoprotein B editing catalytic subunit 1 (APOBEC-1). CDD1 is a yeast ortholog of APOBEC-1 that exhibits cytidine deaminase and RNA-editing activity. Here, we present the crystal structure of CDD1 at 2.0-Å resolution and its use in comparative modeling of APOBEC-1 and AID. The models explain dimerization and the need for trans-acting loops that contribute to active site formation. Substrate selectivity appears to be regulated by a central active site ''flap'' whose size and flexibility accommodate large substrates in contrast to deaminases of pyrimidine metabolism that bind only small nucleosides or free bases. Most importantly, the results suggested both AID and APOBEC-1 are equally likely to bind single-stranded DNA or RNA, which has implications for the identification of natural AID targets.A ntibody diversity is generated during B cell development through class-switch recombination (CSR) and somatic hypermutation (SHM) (1), and in many vertebrates by gene conversion (2). Expression of activation-induced deaminase (AID) is critical for all three processes (3-5) and ectopic AID expression was sufficient to activate SHM in B cell lines, hybridomas, and fibroblasts (6-9), gene conversion in B cells (4, 5), as well as CSR in fibroblast cell lines (10). Mutations in the AID protein have been detected in humans with hyper-IgM type 2 syndrome (11). Expression of AID in Escherichia coli caused deoxycytidine-todeoxyuridine deamination in actively transcribed host genes that was enhanced in strains deficient in the deoxyuridine repair enzyme DNA uracil N-glycosylase (12). DNA uracil N-glycosylase deficiency in mammals resulted in altered patterns of CSR and SHM (13,14). In vitro studies revealed that AID catalyzed deamination on single-stranded DNA at WRCY hot spots, but not on doublestranded DNA, RNA-DNA hybrids, or single-stranded RNA (15,16). Cytidine deamination on single-stranded DNA within transcription bubbles (17, 18) and the observation that transcription rates influenced SHM activity (17)(18)(19) suggested that the biological substrate for AID is DNA.In contrast, the homology of AID to the mRNA-editing enzyme APOBEC-1 (3), suggested AID might edit RNA (3). This idea was intriguing because edited mRNAs either encode novel proteins or lose the ability to express proteins (20,21). Consistent with expression of a novel protein from edited mRNA, de novo protein synthesis was required for CSR subsequent to AID activation (22).APOBEC-1 and AID have proven difficult to purify at levels sufficient for structural studies. CDD1 from Saccharomyces cerevisiae (ScCDD1) can be purified readily, which is relevant due to its orthology with APOBEC-1 at the level of both cytidine deaminase (CDA) sequence similarity (27%) and mRNA-editing activity on apolipoprotein B (apoB) substrates (23). We determined the crystal structure of ScCDD1 to 2.0 Å resolution, which ...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

Xie

Sowden

Dance

et al. 2004

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

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“…Although only distantly related in primary sequence, the enzyme has features that suggest conservation of structure. The E. coli enzyme, like APOBEC3G, is composed of a catalytic domain followed by a topologically similar (␣␤␤␣␤␣␤␤) pseudocatalytic domain and conserves the signature Cys-His Zn 2ϩ coordination motif (15). To determine the approximate position of amino acid 128 on APOBEC3G, we mapped this position onto the E. coli cytidine deaminase structure.…”

Section: Discussionmentioning

confidence: 99%

A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif)

Schröfelbauer

Chen

Landau

2004

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

298

305

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The virion infectivity factor (Vif) accessory protein of HIV-1 forms a complex with the cellular cytidine deaminase APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) to block its antiviral activity. The antiviral property of APOBEC3G is conserved in several mammalian species, but the ability of Vif to block this activity is species-specific. HIV-1 Vif blocks human APOBEC3G but does not block the mouse or African green monkey (AGM) enzyme. Conversely, SIVAGM Vif blocks the antiviral activity of AGM but not human APOBEC3G. We demonstrate that the species specificity is caused by a single amino acid difference in APOBEC3G. Replacement of Asp-128 in human APOBEC3G with the Lys-128 of AGM APOBEC3G caused the enzyme to switch its interaction, becoming sensitive to SIVAGM Vif and resistant to HIV-1 Vif. Conversely, the reciprocal Lys to Asp switch in AGM APOBEC3G reversed its specificity for Vif. The reversal of biological activity was accompanied by the corresponding switch in the species specificity with which the enzyme physically associated with Vif and was excluded from virions. The charge of the amino acid at position 128 was a critical determinant of species specificity. Based on the crystal structure of the distantly related Escherichia coli cytidine deaminase, we propose that this amino acid is positioned on a solvent-exposed loop of APOBEC3G on the same face of the protein as the catalytic site.

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Making Order in the Intrinsically Disordered Regions of HIV‐1 Vif Protein

2011

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Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business

Cited by 269 publications

References 71 publications

The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif)

Making Order in the Intrinsically Disordered Regions of HIV‐1 Vif Protein

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