APOBEC

Last updated
Example of a member of the APOBEC family, APOBEC-2. A cytidine deaminase from Homo sapiens. Apobec.J.Steinfeld.D.png
Example of a member of the APOBEC family, APOBEC-2. A cytidine deaminase from Homo sapiens.
APOBEC-like N-terminal domain
Identifiers
SymbolAPOBEC_N
Pfam PF08210
InterPro IPR013158
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
APOBEC-like C-terminal domain
Identifiers
SymbolAPOBEC_C
Pfam PF05240
InterPro IPR007904
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide") is a family of evolutionarily conserved cytidine deaminases.

Contents

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:

Related Research Articles

Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.

<span class="mw-page-title-main">Activation-induced cytidine deaminase</span> Enzyme that creates mutations in DNA

Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the AICDA gene. It creates mutations in DNA by deamination of cytosine base, which turns it into uracil. In other words, it changes a C:G base pair into a U:G mismatch. The cell's DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During germinal center development of B lymphocytes, error-prone DNA repair following AID action also generates other types of mutations, such as C:G to A:T. AID is a member of the APOBEC family.

<span class="mw-page-title-main">RNA editing</span> Molecular process

RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs. RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.

<span class="mw-page-title-main">Apolipoprotein B</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene. It is commonly used to detect risk of atherosclerotic cardiovascular disease.

<span class="mw-page-title-main">APOBEC3G</span> Protein and coding gene in humans

APOBEC3G is a human enzyme encoded by the APOBEC3G gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in innate anti-viral immunity. APOBEC3G belongs to the family of cytidine deaminases that catalyze the deamination of cytidine to uridine in the single stranded DNA substrate. The C-terminal domain of A3G renders catalytic activity, several NMR and crystal structures explain the substrate specificity and catalytic activity.

Missense mRNA is a messenger RNA bearing one or more mutated codons that yield polypeptides with an amino acid sequence different from the wild-type or naturally occurring polypeptide. Missense mRNA molecules are created when template DNA strands or the mRNA strands themselves undergo a missense mutation in which a protein coding sequence is mutated and an altered amino acid sequence is coded for.

<span class="mw-page-title-main">APOBEC1</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 also known as C->U-editing enzyme APOBEC-1 is a protein that in humans is encoded by the APOBEC1 gene.

<span class="mw-page-title-main">Cytidine deaminase</span> Protein-coding gene in the species Homo sapiens

Cytidine deaminase is an enzyme that in humans is encoded by the CDA gene.

<span class="mw-page-title-main">APOBEC3F</span> Protein-coding gene in the species Homo sapiens

DNA dC->dU-editing enzyme APOBEC-3F is a protein that in humans is encoded by the APOBEC3F gene.

<span class="mw-page-title-main">A1CF</span> Protein-coding gene in the species Homo sapiens

APOBEC1 complementation factor is a protein that in humans is encoded by the A1CF gene.

<span class="mw-page-title-main">APOBEC3C</span> Protein-coding gene in humans

DNA dC->dU-editing enzyme APOBEC-3C is a protein that in humans is encoded by the APOBEC3C gene.

<span class="mw-page-title-main">APOBEC2</span> Protein-coding gene in the species Homo sapiens

Probable C->U-editing enzyme APOBEC-2 is a protein that in humans is encoded by the APOBEC2 gene.

<span class="mw-page-title-main">APOBEC3A</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A, also known as APOBEC3A, or A3A is a gene of the APOBEC3 family found in humans, non-human primates, and some other mammals. It is a single-domain DNA cytidine deaminase with antiviral effects. While other members of the family such as APOBEC3G are believed to act by editing ssDNA by removing an amino group from cytosine in DNA, introducing a cytosine to uracil change which can ultimately lead to a cytosine to thymine mutation, one study suggests that APOBEC3A can inhibit parvoviruses by another mechanism. The cellular function of APOBEC3A is likely to be the destruction of foreign DNA through extensive deamination of cytosine.Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. "APOBEC3 proteins mediate the clearance of foreign DNA from human cells". Nature Structural & Molecular Biology. 17 (2): 222–9. doi:10.1038/nsmb.1744. PMC 2921484. PMID 20062055.

<span class="mw-page-title-main">APOBEC3B</span> Protein-coding gene in the species Homo sapiens

Probable DNA dC->dU-editing enzyme APOBEC-3B is a protein that in humans is encoded by the APOBEC3B gene.

<span class="mw-page-title-main">APOBEC3D</span> Protein-coding gene in the species Homo sapiens

Probable DNA dC->dU-editing enzyme APOBEC-3D is a protein that in humans is encoded by the APOBEC3D gene.

<span class="mw-page-title-main">APOBEC3H</span> Protein-coding gene in the species Homo sapiens

DNA dC->dU-editing enzyme APOBEC-3H, also known as Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3H or APOBEC-related protein 10, is a protein that in humans is encoded by the APOBEC3H gene.

<span class="mw-page-title-main">APOBEC4</span> Protein-coding gene in the species Homo sapiens

C->U-editing enzyme APOBEC-4, also known as Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 4, is a protein that in humans is encoded by the APOBEC4 gene. It is primarily expressed in testis and found in mammals, chicken, but not fishes.

<span class="mw-page-title-main">Kataegis</span>

In molecular biology, kataegis describes a pattern of localized hypermutations identified in some cancer genomes, in which a large number of highly patterned basepair mutations occur in a small region of DNA. The mutational clusters are usually several hundred basepairs long, alternating between a long range of C→T substitutional pattern and a long range of G→A substitutional pattern. This suggests that kataegis is carried out on only one of the two template strands of DNA during replication. Compared to other cancer-related mutations, such as chromothripsis, kataegis is more commonly seen; it is not an accumulative process but likely happens during one cycle of replication.

<span class="mw-page-title-main">Nina Papavasiliou</span> Immunologist

Nina Papavasiliou is an immunologist and Helmholtz Professor in the Division of Immune Diversity at the German Cancer Research Center in Heidelberg, Germany. She is also an adjunct professor at the Rockefeller University, where she was previously associate professor and head of the Laboratory of Lymphocyte Biology. She is best known for her work in the fields of DNA and RNA editing.

Viviana Simon is a Professor of Microbiology at the Icahn School of Medicine at Mount Sinai (ISMMS). She is a member of the ISMMS Global Health and Emerging Pathogens Institute. Her research considers viral-host interactions and the mode of action of retroviral restriction factors. During the COVID-19 pandemic, Simon developed an antibody test that can determine immunity to Coronavirus disease 2019.

References

  1. PDB: 2NYT ; Prochnow C, Bransteitter R, Klein MG, Goodman MF, Chen XS (January 2007). "The APOBEC-2 crystal structure and functional implications for the deaminase AID". Nature. 445 (7126): 447–451. Bibcode:2007Natur.445..447P. doi:10.1038/nature05492. PMID   17187054. S2CID   4394772.; rendered using PyMOL.
  2. Wedekind JE, Dance GS, Sowden MP, Smith HC (April 2003). "Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business". Trends in Genetics. 19 (4): 207–216. doi:10.1016/S0168-9525(03)00054-4. PMID   12683974.
  3. McKusick VA, Hamosh A (19 December 2019) [Originally published 27 September 1994]. "APOLIPOPROTEIN B mRNA-EDITING ENZYME, CATALYTIC POLYPEPTIDE 1; APOBEC1". Online Mendelian Inheritance in Man. Retrieved 23 December 2023.
  4. Blanc V, Davidson NO (January 2003). "C-to-U RNA editing: mechanisms leading to genetic diversity". The Journal of Biological Chemistry. 278 (3): 1395–1398. doi: 10.1074/jbc.r200024200 . PMID   12446660.
  5. 1 2 "Unexpected DNA-Binding Mechanism Suggests Ways to Block Enzyme Activity in Cancer". Dec 2016. Based on ("Structural Basis for Targeted DNA Cytosine Deamination and Mutagenesis by APOBEC3A and APOBEC3B") online in Nature Structural and Molecular Biology.
  6. 1 2 Cervantes-Gracia K, Gramalla-Schmitz A, Weischedel J, Chahwan R (November 2021). "APOBECs orchestrate genomic and epigenomic editing across health and disease". Trends in Genetics. 37 (11): 1028–1043. doi: 10.1016/j.tig.2021.07.003 . PMID   34353635. S2CID   236934922.
  7. Koito A, Ikeda T (2013). "Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases". Frontiers in Microbiology. 4: 28. doi: 10.3389/fmicb.2013.00028 . PMC   3576619 . PMID   23431045.
  8. Butler K, Banday AR (March 2023). "APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential". Journal of Hematology & Oncology. 16 (1): 31. doi: 10.1186/s13045-023-01425-5 . PMC   10044795 . PMID   36978147.
  9. Okazaki IM, Kotani A, Honjo T (2007-01-01). "Role of AID in tumorigenesis". AID for Immunoglobulin Diversity. Advances in Immunology. Vol. 94. Academic Press. pp. 245–273. doi:10.1016/s0065-2776(06)94008-5. ISBN   9780123737069. PMID   17560277.
  10. Vasudevan AA, Smits SH, Höppner A, Häussinger D, Koenig BW, Münk C (November 2013). "Structural features of antiviral DNA cytidine deaminases" (PDF). Biological Chemistry. 394 (11): 1357–1370. doi:10.1515/hsz-2013-0165. PMID   23787464. S2CID   4151961.
This article incorporates text from the public domain Pfam and InterPro: IPR013158