The APOBEC-2 crystal structure and functional implications for the deaminase AID

Prochnow, Courtney; Bransteitter, Ronda; Klein, Michael G.; Goodman, Myron F.; Chen, Xiaojiang S.

doi:10.1038/nature05492

Cited by 189 publications

(245 citation statements)

References 24 publications

Supporting

Mentioning

234

Contrasting

Order By: Relevance

“…Nterminal fusions do not seem to affect AID oligomerization 35 ( Supplementary Fig. 6) or catalytic activity 28,33,35 . Rather, the position of the N-terminus respect to the import determinants suggests that they might be masking the NLS (Fig.…”

Section: Hindered Diffusion Of Aid From the Cytoplasmmentioning

confidence: 94%

“…While investigating the effect of mutations in the putative oligomerization interfaces of AID 33 we found three other Arg residues that were important for nuclear import in addition to Arg50 in FYRN.…”

Section: Aid Has a Conformational Positively Charged Nlsmentioning

confidence: 98%

“…Since protein shape may strongly influence the ability to diffuse 30 , we used APOBEC2 (A2) as control. Given the homology with A2 and APOBEC3G [31][32][33] , the predicted three-dimensional structure of AID safely allows us to postulate that the monomers of A2 (25.7 kDa) and AID (23.9 kDa) will have a similar general folding, and therefore shape ( Supplementary Fig. 1).…”

Section: Aid Is Actively Imported Into the Nucleusmentioning

confidence: 99%

“…AID dimerization through the β2 strand has been proposed based on the structure of A2 33 . We tested the effect of perturbing the predicted AID β2, residues [40][41][42][43][44][45][46][47][48][49][50][51][52][53] in our model, on oligomerization by introducing one (F46A), two (F46A/Y48A) 33 or four (F46A/Y48A/R50G/N51A, named AID FYRN) mutations. The ability of each of these mutants to interact with wt AID was monitored by comparing their efficiency in coimmunoprecipitating with AID-Flag.…”

Section: Aid Has a Conformational Positively Charged Nlsmentioning

confidence: 99%

“…The stoichiometry and architecture of the biologically relevant AID molecule is unknown but many indirect evidences suggest that it will have quaternary structure 33,35,42,47,48 as all cytidine deaminases including the APOBECs do 33,49,50 . Predicting AID dimerization through β2 (ref.…”

Section: Active Nuclear Import Of Aidmentioning

confidence: 99%

See 4 more Smart Citations

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Patenaude

Orthwein

et al. 2009

Nat Struct Mol Biol

134

175

View full text Add to dashboard Cite

The enzyme Activation Induced Deaminase (AID) triggers antibody diversification in B-cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, its nuclear entry requiring active import mediated by a conformational nuclear localization sequence (NLS). We also identify a determinant for AID cytoplasmic retention in its Cterminus, which hampers diffusion to the nucleus, competes with nuclear import and is critical for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.3

show abstract

Section: Hindered Diffusion Of Aid From the Cytoplasmmentioning

confidence: 94%

Section: Aid Has a Conformational Positively Charged Nlsmentioning

confidence: 98%

Section: Aid Is Actively Imported Into the Nucleusmentioning

confidence: 99%

Section: Aid Has a Conformational Positively Charged Nlsmentioning

confidence: 99%

Section: Active Nuclear Import Of Aidmentioning

confidence: 99%

See 3 more Smart Citations

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Patenaude

Orthwein

et al. 2009

Nat Struct Mol Biol

134

175

View full text Add to dashboard Cite

show abstract

Structural plasticity of substrate selection by activation‐induced cytidine deaminase as a regulator of its genome‐wide mutagenic activity

King

Larijani

2020

FEBS Letters

View full text Add to dashboard Cite

Activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class-switch recombination of antibodies. Computational-biochemical and crystallography analyses of AID have identified three surface grooves for binding single-stranded DNA (ssDNA). Functional studies have also found evidence for RNA-binding motifs on AID. Although AID and the related apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APO-BEC) enzymes share a conserved core, AID uniquely features multiple substrate-binding motifs on its surface. Here we suggest that combinatorial deployment of AID's multiple ssDNA-or RNA-binding motifs yields many substrate-binding modes that can accommodate ssDNA, RNA, or DNA/RNA substrates of diverse structures. We also suggest that AID oligomerization generates yet additional novel substrate-binding modes. We propose that this plasticity in substrate choice is an evolved aspect of AID's structure that contributes to the regulation of its differential mutagenic activity at various loci.

show abstract

Identifying genetic susceptibility to Aspergillus fumigatus infection using collaborative cross mice and RNA‐Seq approach

Yosief,

Lone,

Nachshon

et al. 2024

Anim Models and Exp Med

View full text Add to dashboard Cite

BackgroundAspergillus fumigatus (Af) is one of the most ubiquitous fungi and its infection potency is suggested to be strongly controlled by the host genetic background. The aim of this study was to search for candidate genes associated with host susceptibility to Aspergillus fumigatus (Af) using an RNAseq approach in CC lines and hepatic gene expression.MethodsWe studied 31 male mice from 25 CC lines at 8 weeks old; the mice were infected with Af. Liver tissues were extracted from these mice 5 days post‐infection, and next‐generation RNA‐sequencing (RNAseq) was performed. The GENE‐E analysis platform was used to generate a clustered heat map matrix.ResultsSignificant variation in body weight changes between CC lines was observed. Hepatic gene expression revealed 12 top prioritized candidate genes differentially expressed in resistant versus susceptible mice based on body weight changes. Interestingly, three candidate genes are located within genomic intervals of the previously mapped quantitative trait loci (QTL), including Gm16270 and Stox1 on chromosome 10 and Gm11033 on chromosome 8.ConclusionsOur findings emphasize the CC mouse model's power in fine mapping the genetic components underlying susceptibility towards Af. As a next step, eQTL analysis will be performed for our RNA‐Seq data. Suggested candidate genes from our study will be further assessed with a human cohort with aspergillosis.

show abstract

The APOBEC-2 crystal structure and functional implications for the deaminase AID

Cited by 189 publications

References 24 publications

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Structural plasticity of substrate selection by activation‐induced cytidine deaminase as a regulator of its genome‐wide mutagenic activity

Identifying genetic susceptibility to Aspergillus fumigatus infection using collaborative cross mice and RNA‐Seq approach

Contact Info

Product

Resources

About