5jj4

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Crystal Structure of a Variant Human Activation-induced Deoxycytidine Deaminase as an MBP fusion proteinCrystal Structure of a Variant Human Activation-induced Deoxycytidine Deaminase as an MBP fusion protein

Structural highlights

5jj4 is a 3 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 2.807Å
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

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] MALE_ECO57 Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity).

Publication Abstract from PubMed

Activation-induced deoxycytidine deaminase (AID) initiates somatic hypermutation (SHM) and class-switch recombination (CSR) by deaminating C-->U during transcription of Ig-variable (V) and Ig-switch (S) region DNA, which is essential to produce high-affinity antibodies. Here we report the crystal structure of a soluble human AID variant at 2.8A resolution that favors targeting WRC motifs (W=A/T, R=A/G) in vitro, and executes Ig V SHM in Ramos B-cells. A specificity loop extending away from the active site to accommodate two purine bases next to C, differs significantly in sequence, length, and conformation from APOBEC proteins Apo3A and Apo3G, which strongly favor pyrimidines at -1 and -2 positions. Individual amino acid contributions to specificity and processivity were measured in relation to a proposed ssDNA binding cleft. This study provides a structural basis for residue contributions to DNA scanning properties unique to AID, and for disease mutations in human HIGM-2 syndrome.

Structural analysis of the activation-induced deoxycytidine deaminase required in immunoglobulin diversification.,Pham P, Afif SA, Shimoda M, Maeda K, Sakaguchi N, Pedersen LC, Goodman MF DNA Repair (Amst). 2016 Jul;43:48-56. doi: 10.1016/j.dnarep.2016.05.029. Epub, 2016 May 13. PMID:27258794[6]

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

References

  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. ↑ Pham P, Afif SA, Shimoda M, Maeda K, Sakaguchi N, Pedersen LC, Goodman MF. Structural analysis of the activation-induced deoxycytidine deaminase required in immunoglobulin diversification. DNA Repair (Amst). 2016 Jul;43:48-56. doi: 10.1016/j.dnarep.2016.05.029. Epub, 2016 May 13. PMID:27258794 doi:http://dx.doi.org/10.1016/j.dnarep.2016.05.029

5jj4, resolution 2.81Å

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