Activation-induced cytidine deaminase

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Activation-induced cytidine deaminase
Properties of human protein
Mass / length primary structure 198 amino acids
Cofactor Zn 2+
Identifier
Gene name AICDA
External IDs
Enzyme classification
EC, category 3.5.4.38 ,  aminohydrolase
Response type hydrolysis
Substrate ss-DNA-cytidine + H 2 O
Products ss-DNA-uridine + NH 3
Occurrence
Parent taxon Vertebrates
Orthologue
human House mouse
Entrez 57379 11628
Ensemble ENSG00000111732 ENSMUSG00000040627
UniProt Q9GZX7 Q9WVE0
Refseq (mRNA) NM_020661 NM_009645
Refseq (protein) NP_065712 NP_033775
Gene locus Chr 12: 8.6 - 8.61 Mb Chr 6: 122.55 - 122.56 Mb
PubMed search 57379 11628

The activation-induced cytidine deaminase (AID, engl. Activation-induced cytidine deaminase ) is an enzyme which in B-lymphocytes of vertebrates is expressed. It specifically catalyzes the hydrolysis of cytidine residues to uridine residues , which are bound to single-stranded DNA . The AID has the task during the hypermutation the antibody sequences of the B-cells to mutate and thereby alter the binding properties of the antibody produced therefrom. As a result, AID is an important component in the maturation of high-affinity antibodies and a key enzyme of the adaptive immune response.

Mutations of AICDA - gene in humans are AID deficiency and this for the rare inherited disorder hyper-IgM syndrome , responsible type 2 (HIGM2), an immune deficiency.

The role of AID in the polymorphism of antibodies in the immune system was discovered by Michael Neuberger .

Role of AID in the adaptive immune system

The main function of AID is to change the immunoglobulin genes (Ig genes). There are three possibilities: hypermutation, class-switch recombination and gene conversion. All three processes are regulated and controlled centrally by the AID. All three processes have different effects on the antibody sequences:

  • Hypermutation : Hypermutation is the central process of antibody maturation. The antibody sequences are mutated by the AID. The hypermutation can only be found in the B lymphocytes, but not in T lymphocytes .
  • Class-switch recombination : The class-switch recombination is used to change the effector function in the constant areas of the antibodies. Certain sequence areas recombine between constant regions of the antibody sequences and thus cause the change in the effector function.
  • Gene conversion : Gene conversion occurs, for example, in chickens to produce the diversity of antibodies. This is a homologous recombination with pseudo-V genes induced by the AID.

structure

The AID is a 28 kDa protein and closely related to APOBEC1 ( apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide ). The structure of the AID is highly conserved. It contains a cytidine deaminase motif, a C-terminal APOBEC-like motif, a C-terminal NES (Engl. N uclear E xport S equence ) and a non-functional N-termiale NLS (Engl. N uclear I mport S equence ). The three-dimensional structure of the AID has not yet been clarified.

Specificity of the AID

To this day, there are only contradicting views about the specificity of AID. What is certain is that the AID only recognizes single-stranded DNA. For this reason, only strongly transcribed DNA sequences are strongly mutated, since these are increasingly single-stranded. Due to the functionless NLS and the NES, the AID is increasingly transported from the cell nucleus, the place of transcription. The reason why it is still present in the cell nucleus is the small size of 28 kDa. This allows the AID to diffuse through the nuclear pore complexes . It has been shown that AID mutates more cytidine in so-called hotspots. These hotspots are short sequence motifs with the following sequence: WRCY, where W stands for A or T and Y for pyrimidines and R for purines. Furthermore, the chromatin structure and the interaction with other factors are also held responsible for the specificity of AID. However, a final clarification is still pending.

Application of the AID

The AID is already being used to induce antibody maturation in CHO cells . The cells are transfected with the AID and the cells that bind better to the antigen via their antibodies are selected. For this purpose, the antigen is marked with a fluorescent dye and the cells are sorted using fluorescence activated cell sorting (FACS).

The AID as a central component for the iGEM project 2012 at the University of Potsdam

The iGEM team 2012 at the University of Potsdam has also dedicated itself to this topic. The goal of the team is to develop a system with which CHO cells, triggered by viral influence, form high-affinity antibodies. The system should be chosen so that cells with the highest affinity antibody, which represents an optimal adaptation to the selection pressure. For this purpose, the AID is transiently transfected into the CHO cells and thus the hypermutation is triggered. The cells that produce an antibody with a higher affinity bind better to the virus and thus receive a survival signal. This makes it (theoretically) possible to form high-affinity antibodies. The advantage of the system is that immunization of a mammal, e.g. B. a mouse, for the production of antibodies is thus unnecessary. Whether the cells really produce higher affinity antibodies through the selection pressure of the viruses remains to be proven.

literature

Individual evidence

  1. ↑ M. Larijani, AP Petrov et al. a .: AID associates with single-stranded DNA with high affinity and a long complex half-life in a sequence-independent manner. In: Molecular and cellular biology. Vol. 27, No. 1, January 2007, pp. 20-30, ISSN  0270-7306 . doi : 10.1128 / MCB.00824-06 . PMID 17060445 . PMC 1800660 (free full text).
  2. ↑ OrphaNet: Hyper-IgM Syndrome Type 2

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