| Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. | |
| | |
MedLine Citation:
|
PMID: 20929867 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Nucleic acid cytidine deaminases of the activation-induced deaminase (AID)/APOBEC family are critical players in active and innate immune responses, playing roles as target-directed, purposeful mutators. AID specifically deaminates the host immunoglobulin (Ig) locus to evolve antibody specificity, whereas its close relative, APOBEC3G (A3G), lethally mutates the genomes of retroviral pathogens such as HIV. Understanding the basis for the target-specific action of these enzymes is essential, as mistargeting poses significant risks, potentially promoting oncogenesis (AID) or fostering drug resistance (A3G). AID prefers to deaminate cytosine in WRC (W = A/T, R = A/G) motifs, whereas A3G favors deamination of CCC motifs. This specificity is largely dictated by a single, divergent protein loop in the enzyme family that recognizes the DNA sequence. Through grafting of this substrate-recognition loop, we have created enzyme variants of A3G and AID with altered local targeting to directly evaluate the role of sequence specificity on immune function. We find that grafted loops placed in the A3G scaffold all produced efficient restriction of HIV but that foreign loops in the AID scaffold compromised hypermutation and class switch recombination. Local targeting, therefore, appears alterable for innate defense against retroviruses by A3G but important for adaptive antibody maturation catalyzed by AID. Notably, AID targeting within the Ig locus is proportionally correlated to its in vitro ability to target WRC sequences rather than non-WRC sequences. Although other mechanisms may also contribute, our results suggest that local sequence targeting by AID/APOBEC3 enzymes represents an elegant example of co-evolution of enzyme specificity with its target DNA sequence. |
| | |
Authors:
|
Rahul M Kohli; Robert W Maul; Amy F Guminski; Rhonda L McClure; Kiran S Gajula; Huseyin Saribasak; Moira A McMahon; Robert F Siliciano; Patricia J Gearhart; James T Stivers |
Related Documents
:
|
20508977 - Children's psychosocial problems presenting in a family medicine practice. 3678697 - Perceptions and treatment of sexual problems. 19202597 - Crosstalk between the sumo and ubiquitin pathways. 12295867 - Samoa: the realities of living with hiv in samoa. 910987 - Suicide among police. 16374657 - The four es of problem gambling: a psychological measure of risk. |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural Date: 2010-10-06 |
Journal Detail:
|
Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Dec |
Date Detail:
|
Created Date: 2010-12-20 Completed Date: 2011-01-24 Revised Date: 2011-12-26 |
Medline Journal Info:
|
Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 40956-64 Citation Subset: IM |
Affiliation:
|
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Amino Acid Motifs Animals Antibodies, Viral / genetics, metabolism* B-Lymphocytes / metabolism Cytidine Deaminase / genetics, metabolism* Evolution, Molecular HEK293 Cells HIV Infections / enzymology*, genetics HIV-1 / genetics, metabolism* Humans Immunity, Innate Mice Mice, Knockout Protein Structure, Secondary |
| Grant Support | |
ID/Acronym/Agency:
|
GM056834/GM/NIGMS NIH HHS; KAI089242A//PHS HHS; T32 GM06669/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Antibodies, Viral; EC 3.5.4.-/AICDA (activation-induced cytidine deaminase); EC 3.5.4.5/APOBEC3G protein, human; EC 3.5.4.5/Cytidine Deaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Separate and combined biochemical activities of the subunits of a naturally split reverse gyrase.
Next Document: DBASS3 and DBASS5: databases of aberrant 3'- and 5'-splice sites.