Biology:APOBEC
300px|thumb|upright|Example of a member of the APOBEC family, APOBEC-2. A cytidine deaminase from Homo sapiens.[1]
| APOBEC-like N-terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | APOBEC_N | ||||||||
| Pfam | PF08210 | ||||||||
| InterPro | IPR013158 | ||||||||
| |||||||||
| APOBEC-like C-terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | APOBEC_C | ||||||||
| Pfam | PF05240 | ||||||||
| InterPro | IPR007904 | ||||||||
| |||||||||
APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide") is a family of evolutionarily conserved cytidine deaminases.
Function
A mechanism of generating protein diversity is mRNA editing. The APOBEC family of proteins perform mRNA modifications by deaminating cytidine bases to uracil. The N-terminal domain of APOBEC-like proteins is the catalytic domain, while the C-terminal domain is a pseudocatalytic domain. More specifically, the catalytic domain is a zinc dependent cytidine deaminase domain and is essential for cytidine deamination. The positively charged zinc ion in the catalytic domain attracts to the partial-negative charge of RNA.
In the case of APOBEC-1, the mRNA transcript of intestinal apolipoprotein B is altered. RNA editing by APOBEC-1 requires homodimerization and this complex interacts with RNA-binding proteins to form the editosome.[2] The resulting structure interacts with the codon CAA at codon 2153 and deaminates it into UAA, producing a stop codon that results in mRNA that is translated into the intestinal apoB-48 isoform.[3] For other APOBEC-modified transcripts such as in the site-specific deamination of a CGA to a UGA stop codon in neurofibromatosis type 1 (NF1) mRNA, the resulting proteins are predicted to be truncated as well, although these transcripts are possibly degraded.[4]
C-to-U modifications do not always result in the truncation of proteins. For example, in humans/mammals they help protect from viral infections.[5][6] APOBEC family proteins are widely expressed in cells of the human innate immune system.[7]
Cancer
These enzymes, when misregulated, are a major source of mutation in numerous cancer types.[5][6][8] When the expression of APOBEC family proteins is triggered, accidental mutations in somatic cells can lead to the development of oncogenes, cells which have the potential to develop into a tumor. APOBEC proteins are further expressed in attempt to regulate tumor formation. This makes APOBEC proteins a helpful marker for diagnosing malignant tumors.[9]
Structure
A 2013 review discussed the structural and biophysical aspects of APOBEC3 family enzymes.[10] Many of the APOBEC protein features are described in the widely studied APOBEC3G's page.[tone]
Family members
Human genes encoding members of the APOBEC protein family include:
- APOBEC1
- APOBEC2
- APOBEC3A
- APOBEC3B
- APOBEC3C
- APOBEC3D ("APOBEC3E" now refers to this)
- APOBEC3F
- APOBEC3G
- APOBEC3H
- APOBEC4
- Activation-induced (cytidine) deaminase (AID)
References
- ↑ PDB: 2NYT; "The APOBEC-2 crystal structure and functional implications for the deaminase AID". Nature 445 (7126): 447–451. January 2007. doi:10.1038/nature05492. PMID 17187054. Bibcode: 2007Natur.445..447P.; rendered using PyMOL.
- ↑ "Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business". Trends in Genetics 19 (4): 207–216. April 2003. doi:10.1016/S0168-9525(03)00054-4. PMID 12683974.
- ↑ "APOLIPOPROTEIN B mRNA-EDITING ENZYME, CATALYTIC POLYPEPTIDE 1; APOBEC1". 19 December 2019. https://www.omim.org/entry/600130.
- ↑ "C-to-U RNA editing: mechanisms leading to genetic diversity". The Journal of Biological Chemistry 278 (3): 1395–1398. January 2003. doi:10.1074/jbc.r200024200. PMID 12446660.
- ↑ 5.0 5.1 "Unexpected DNA-Binding Mechanism Suggests Ways to Block Enzyme Activity in Cancer". Dec 2016. http://www.genengnews.com/gen-news-highlights/unexpected-dna-binding-mechanism-suggests-ways-to-block-enzyme-activity-in-cancer/81253584. "Based on ("Structural Basis for Targeted DNA Cytosine Deamination and Mutagenesis by APOBEC3A and APOBEC3B") online in Nature Structural and Molecular Biology."
- ↑ 6.0 6.1 "APOBECs orchestrate genomic and epigenomic editing across health and disease". Trends in Genetics 37 (11): 1028–1043. November 2021. doi:10.1016/j.tig.2021.07.003. PMID 34353635.
- ↑ "Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases". Frontiers in Microbiology 4: 28. 2013. doi:10.3389/fmicb.2013.00028. PMID 23431045.
- ↑ "APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential". Journal of Hematology & Oncology 16 (1): 31. March 2023. doi:10.1186/s13045-023-01425-5. PMID 36978147.
- ↑ "Role of AID in tumorigenesis". Advances in Immunology. AID for Immunoglobulin Diversity (Academic Press) 94: 245–273. 2007-01-01. doi:10.1016/s0065-2776(06)94008-5. ISBN 9780123737069. PMID 17560277.
- ↑ "Structural features of antiviral DNA cytidine deaminases". Biological Chemistry 394 (11): 1357–1370. November 2013. doi:10.1515/hsz-2013-0165. PMID 23787464.
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