5w0r

Crystal structure of MBP fused activation-induced cytidine deaminase (AID) in complex with cacodylic acidCrystal structure of MBP fused activation-induced cytidine deaminase (AID) in complex with cacodylic acid

Structural highlights

5w0r is a 2 chain structure with sequence from Escherichia coli O157:H7 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AICDA_HUMAN Hyper-IgM syndrome type 2. The disease is caused by mutations affecting the gene represented in this entry.

Function

MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.AICDA_HUMAN Single-stranded DNA-specific cytidine deaminase. Involved in somatic hypermutation (SHM), gene conversion, and class-switch recombination (CSR) in B-lymphocytes by deaminating C to U during transcription of Ig-variable (V) and Ig-switch (S) region DNA. Required for several crucial steps of B-cell terminal differentiation necessary for efficient antibody responses (PubMed:18722174, PubMed:21385873, PubMed:21518874, PubMed:27716525). May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation (PubMed:21496894).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Activation-induced cytidine deaminase (AID) initiates both class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. Mechanisms of AID targeting and catalysis remain elusive despite its critical immunological roles and off-target effects in tumorigenesis. Here, we produced active human AID and revealed its preferred recognition and deamination of structured substrates. G-quadruplex (G4)-containing substrates mimicking the mammalian immunoglobulin switch regions are particularly good AID substrates in vitro. By solving crystal structures of maltose binding protein (MBP)-fused AID alone and in complex with deoxycytidine monophosphate, we surprisingly identify a bifurcated substrate-binding surface that explains structured substrate recognition by capturing two adjacent single-stranded overhangs simultaneously. Moreover, G4 substrates induce cooperative AID oligomerization. Structure-based mutations that disrupt bifurcated substrate recognition or oligomerization both compromise CSR in splenic B cells. Collectively, our data implicate intrinsic preference of AID for structured substrates and uncover the importance of G4 recognition and oligomerization of AID in CSR.

AID Recognizes Structured DNA for Class Switch Recombination.,Qiao Q, Wang L, Meng FL, Hwang JK, Alt FW, Wu H Mol Cell. 2017 Aug 3;67(3):361-373.e4. doi: 10.1016/j.molcel.2017.06.034. Epub, 2017 Jul 27. PMID:28757211^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Conticello SG, Ganesh K, Xue K, Lu M, Rada C, Neuberger MS. Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1. Mol Cell. 2008 Aug 22;31(4):474-84. doi: 10.1016/j.molcel.2008.07.009. PMID:18722174 doi:10.1016/j.molcel.2008.07.009
↑ Ganesh K, Adam S, Taylor B, Simpson P, Rada C, Neuberger M. CTNNBL1 is a novel nuclear localization sequence-binding protein that recognizes RNA-splicing factors CDC5L and Prp31. J Biol Chem. 2011 May 13;286(19):17091-102. doi: 10.1074/jbc.M110.208769. Epub, 2011 Mar 8. PMID:21385873 doi:http://dx.doi.org/10.1074/jbc.M110.208769
↑ Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr, 14. PMID:21496894 doi:10.1016/j.cell.2011.03.022
↑ Okazaki IM, Okawa K, Kobayashi M, Yoshikawa K, Kawamoto S, Nagaoka H, Shinkura R, Kitawaki Y, Taniguchi H, Natsume T, Iemura S, Honjo T. Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7920-5. doi:, 10.1073/pnas.1104423108. Epub 2011 Apr 25. PMID:21518874 doi:http://dx.doi.org/10.1073/pnas.1104423108
↑ Ouadani H, Ben-Mustapha I, Ben-Ali M, Largueche B, Jovanic T, Garcia S, Arcangioli B, Elloumi-Zghal H, Fathallah D, Hachicha M, Masmoudi H, Rougeon F, Barbouche MR. Activation induced cytidine deaminase mutant (AID-His130Pro) from Hyper IgM 2 patient retained mutagenic activity on SHM artificial substrate. Mol Immunol. 2016 Nov;79:77-82. doi: 10.1016/j.molimm.2016.09.025. Epub 2016 Oct , 4. PMID:27716525 doi:http://dx.doi.org/10.1016/j.molimm.2016.09.025
↑ Qiao Q, Wang L, Meng FL, Hwang JK, Alt FW, Wu H. AID Recognizes Structured DNA for Class Switch Recombination. Mol Cell. 2017 Aug 3;67(3):361-373.e4. doi: 10.1016/j.molcel.2017.06.034. Epub, 2017 Jul 27. PMID:28757211 doi:http://dx.doi.org/10.1016/j.molcel.2017.06.034

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OCA

[1] Conticello SG, Ganesh K, Xue K, Lu M, Rada C, Neuberger MS. Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1. Mol Cell. 2008 Aug 22;31(4):474-84. doi: 10.1016/j.molcel.2008.07.009. PMID:18722174 doi:10.1016/j.molcel.2008.07.009

[2] Ganesh K, Adam S, Taylor B, Simpson P, Rada C, Neuberger M. CTNNBL1 is a novel nuclear localization sequence-binding protein that recognizes RNA-splicing factors CDC5L and Prp31. J Biol Chem. 2011 May 13;286(19):17091-102. doi: 10.1074/jbc.M110.208769. Epub, 2011 Mar 8. PMID:21385873 doi:http://dx.doi.org/10.1074/jbc.M110.208769

[3] Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr, 14. PMID:21496894 doi:10.1016/j.cell.2011.03.022

[4] Okazaki IM, Okawa K, Kobayashi M, Yoshikawa K, Kawamoto S, Nagaoka H, Shinkura R, Kitawaki Y, Taniguchi H, Natsume T, Iemura S, Honjo T. Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7920-5. doi:, 10.1073/pnas.1104423108. Epub 2011 Apr 25. PMID:21518874 doi:http://dx.doi.org/10.1073/pnas.1104423108

[5] Ouadani H, Ben-Mustapha I, Ben-Ali M, Largueche B, Jovanic T, Garcia S, Arcangioli B, Elloumi-Zghal H, Fathallah D, Hachicha M, Masmoudi H, Rougeon F, Barbouche MR. Activation induced cytidine deaminase mutant (AID-His130Pro) from Hyper IgM 2 patient retained mutagenic activity on SHM artificial substrate. Mol Immunol. 2016 Nov;79:77-82. doi: 10.1016/j.molimm.2016.09.025. Epub 2016 Oct , 4. PMID:27716525 doi:http://dx.doi.org/10.1016/j.molimm.2016.09.025

[6] Qiao Q, Wang L, Meng FL, Hwang JK, Alt FW, Wu H. AID Recognizes Structured DNA for Class Switch Recombination. Mol Cell. 2017 Aug 3;67(3):361-373.e4. doi: 10.1016/j.molcel.2017.06.034. Epub, 2017 Jul 27. PMID:28757211 doi:http://dx.doi.org/10.1016/j.molcel.2017.06.034

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