The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation

Uttiya Basu, Jayanta Chaudhuri, Craig Alpert, Shilpee Dutt, Sheila Ranganath, Gang Li, Jason Patrick Schrum, John P. Manis and Frederick W. Alt ()
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Uttiya Basu: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School
Jayanta Chaudhuri: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School
Craig Alpert: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School
Shilpee Dutt: Harvard Medical School
Sheila Ranganath: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School
Gang Li: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School
Jason Patrick Schrum: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School
John P. Manis: Harvard Medical School
Frederick W. Alt: The CBR Institute for Biomedical Research, and Department of Genetics, Harvard Medical School

Nature, 2005, vol. 438, issue 7067, 508-511

Abstract: Abstract Antibodies, which are produced by B-lineage cells, consist of immunoglobulin heavy (IgH) and light (IgL) chains that have amino-terminal variable regions and carboxy-terminal constant regions. In response to antigens, B cells undergo two types of genomic alterations to increase antibody diversity. Affinity for antigen can be increased by introduction of point mutations into IgH and IgL variable regions by somatic hypermutation. In addition, antibody effector functions can be altered by changing the expressed IgH constant region exons through IgH class switch recombination (CSR)1,2,3. Somatic hypermutation and CSR both require the B-cell-specific activation-induced cytidine deaminase protein (AID)4,5,6, which initiates these reactions through its single-stranded (ss)DNA-specific cytidine deaminase activity7,8,9,10,11. In biochemical assays, replication protein A (RPA), a ssDNA-binding protein12, associates with phosphorylated AID from activated B cells and enhances AID activity on transcribed double-stranded (ds)DNA containing somatic hypermutation or CSR target sequences. This AID–RPA association, which requires phosphorylation, may provide a mechanism for allowing AID to access dsDNA targets in activated B cells13,14. Here we show that AID from B cells is phosphorylated on a consensus protein kinase A (PKA) site and that PKA is the physiological AID kinase. Thus, AID from non-lymphoid cells can be functionally phosphorylated by recombinant PKA to allow interaction with RPA and promote deamination of transcribed dsDNA substrates. Moreover, mutation of the major PKA phosphorylation site of AID preserves ssDNA deamination activity, but markedly reduces RPA-dependent dsDNA deamination activity and severely impairs the ability of AID to effect CSR in vivo. We conclude that PKA has a critical role in post-translational regulation of AID activity in B cells.

Date: 2005
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DOI: 10.1038/nature04255

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