APOBEC1

Last updated
APOBEC1
Identifiers
Aliases APOBEC1 , APOBEC-1, BEDP, CDAR1, HEPR, apolipoprotein B mRNA editing enzyme catalytic subunit 1
External IDs OMIM: 600130 MGI: 103298 HomoloGene: 1243 GeneCards: APOBEC1
Orthologs
SpeciesHumanMouse
Entrez

339

11810

Ensembl

ENSG00000111701

ENSMUSG00000040613

UniProt

P41238

P51908

RefSeq (mRNA)

NM_005889
NM_001304566
NM_001644

NM_001134391
NM_031159

RefSeq (protein)

NP_001291495
NP_001635
NP_005880

NP_001127863
NP_112436

Location (UCSC) Chr 12: 7.65 – 7.67 Mb Chr 6: 122.55 – 122.58 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5]

Contents

This gene encodes a member of the APOBEC protein family and the cytidine deaminase enzyme family. The encoded protein forms a multiple-protein RNA editing holoenzyme with APOBEC1 complementation factor (A1CF). This holoenzyme is involved in the editing of cytosine-to-uracil (C-to-U) nucleotide bases in apolipoprotein B and neurofibromin 1 mRNAs. [5]

APOBEC-1 (A1) has been linked with cholesterol control, cancer development and inhibition of viral replication. [6] Its function relies on introducing a stop codon into apolipoprotein B (ApoB) mRNA, which alters lipid metabolism in the gastrointestinal tract. The editing mechanism is highly specific. A1’s deamination of the cytosine base yields uracil, which creates a stop codon in the mRNA.

The overall deamination of cytidine to form uridine. Deamination of cytidine.png
The overall deamination of cytidine to form uridine.

A1 has been linked with both positive and negative health effects. In rodents, it has wide tissue distribution where as in humans, it is only expressed in the small intestine. [7]

Gene

APOBEC1 lies on human chromosome 12. [8]

Function

ApoB is essential in the assembly of very low density lipoproteins from lipids, in the liver and small intestine. [7] By editing ApoB, it forces only the smaller product, ApoB48, to be expressed, which greatly inhibits lipoprotein production. However, A1 is currently found only at extremely low levels in the human liver and intestine, while it is highly expressed in rodents. In humans, A1 is found exclusively in gastrointestinal epithelial cells. [6]

Mechanism

A1 modifies the cytosine base at position 6666 on the ApoB mRNA strand through a deamination. [9] An A1 dimer first binds to ACF, which forms the binding complex that is then able to eliminate the amine group from cytosine.

These residues (Leu-182 to Pro-191) are necessary for dimerization of APOBEC1, which is necessary to form the correct enzyme complex with ACF. During experimentation, substituted leucine and isoleucine residues significantly reduced the deamination of cytosine. Dimerization Portion of APOBEC1.png
These residues (Leu-182 to Pro-191) are necessary for dimerization of APOBEC1, which is necessary to form the correct enzyme complex with ACF. During experimentation, substituted leucine and isoleucine residues significantly reduced the deamination of cytosine.

ACF binds to the mooring sequence, which puts A1 in position to edit the correct residue. [10] By converting cytosine to uracil, A1 changes the codon from CAA, which codes for glutamine during transcription, to UAA, a stop codon. [11] This stop codon yields the much shorter protein ApoB48 instead of ApoB100, as the mRNA is predisposed to transcript. [12] The editing amount, or expression, of A1 performs is correlated with the insulin concentration in the nucleus, the site of modification. [13] [14] Tests involving A1 mutants with various deleted amino acid sequences have shown that editing activity is dependent on residues 14 to 35. Like all APOBEC proteins, A1 coordinates a zinc atom with two cysteine and one histidine residues that serve as a Lewis acid. Hydrolytic deamination of the cytosine amine group then occurs, catalyzed by the proton transfer from the nearby glutamic acid residue, and the enzymatic structure is conserved by a proline residue. [10]

Possible mechanism for C-to-U modification using Zinc complex with H-66, Cys-93, and Cys-96. C-to-U mechanism.png
Possible mechanism for C-to-U modification using Zinc complex with H-66, Cys-93, and Cys-96.

Structure

The structure of A1 relies on three dimensional folds induced by a zinc complex. [15] These folds allow the enzyme to access the RNA specifically. Deletion tests with mutant strands have shown that residues 181 to 210 are integral to mRNA editing, and there is most likely a beta-turn at proline residues 190 and 191. [10] Specifically, L182, I185, and L189 are integral to the complex’s function, most likely due to their importance to dimerization. [10] Substituting these residues has no predicted impact on secondary structure, so the significant decrease in editing activity is best explained by the alteration of the side-chains, which are integral to dimer structure. [10] Amino acid replacements at these sites deactivated deamination. The C-terminal of enzyme structure is more strongly expressed in the nucleus, hence the site of modification, while the 181 to 210 residues indicate that the enzyme is in the cytoplasm. These are regulatory factors. [16]

APOBEC1 catalytic active site, residue regionResidues 59-70, 82-95Linking glycine represents residues 71-81, which are not related to activation APOBEC1 Catalytic Site.png
APOBEC1 catalytic active site, residue regionResidues 59-70, 82-95Linking glycine represents residues 71-81, which are not related to activation

Disease relevance

The low levels of A1 in humans are one reason why high lipid intake is damaging to health. ApoB48 is essential for the assembly and secretion of triglyceride-rich chylomicrons, which are necessary as a response to high-fat intake. ApoB100 are metabolized in the bloodstream to LDL cholesterol, [17] high levels of which are associated with atherosclerosis. [18] While A1 has a negligible impact on human lipid synthesis, at high concentrations it can be genotoxic. Its diffusion toward the nucleic membrane can lead it to mutate DNA sequences that are actively transcribed on the genome. In single growth assays, A1 has been found to impact HIV replications. Additionally, A1 has reduced Hepatitis B virus (HBV) DNA replication, although the mechanism is still not known. The antiviral properties of A1 extend to both DNA and RNA due to its deamination function, which can hinder DNA replication and consequently suppress further infection by HIV or HBV. [19] A pan-cancer study shows that A1 mRNA level is associated with adverse prognosis as well as higher rate of the human genomic insertions and deletions (indels), particularly in-frame ones, which proposes its endogenous mutator activity. [20] There has also been evidence that A1 also edits at NF1, related to tumors in nerve cells. [21]

Interactions

APOBEC1 has been shown to interact with:

See also

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, AID also generates other types of mutations, such as C:G to A:T. The mechanism by which these other mutations are created is not well understood. It is a member of the APOBEC family.

<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.

<span class="mw-page-title-main">Phospholipid transfer protein</span> Mammalian protein found in Homo sapiens

Phospholipid transfer protein is a protein that in humans is encoded by the PLTP gene.

<span class="mw-page-title-main">Microsomal triglyceride transfer protein</span>

Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP gene.

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

Synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP), also known as heterogeneous nuclear ribonucleoprotein (hnRNP) Q or NS1-associated protein-1 (NSAP-1), is a protein that in humans is encoded by the SYNCRIP gene. As the name implies, SYNCRIP is localized predominantly in the cytoplasm. It is evolutionarily conserved across eukaryotes and participates in several cellular and disease pathways, especially in neuronal and muscular development. In humans, there are three isoforms, all of which are associated in vitro with pre-mRNAs, mRNA splicing intermediates, and mature mRNA-protein complexes, including mRNA turnover.

<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">CUGBP2</span> Protein-coding gene in the species Homo sapiens

CUGBP, Elav-like family member 2, also known as Etr-3 is a protein that in humans is encoded by the CELF2 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">BAG4</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 4 is a protein that in humans is encoded by the BAG4 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">APOBEC</span> Enzyme involved in messenger RNA editing

APOBEC is a family of evolutionarily conserved cytidine deaminases.

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

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<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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000111701 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040613 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: APOBEC1 apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1".
  6. 1 2 Rosenberg BR, Hamilton CE, Mwangi MM, Dewell S, Papavasiliou FN (2011). "Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3' UTRs". Nat. Struct. Mol. Biol. 18 (2): 230–6. doi:10.1038/nsmb.1975. PMC   3075553 . PMID   21258325.
  7. 1 2 Teng BB, Ochsner S, Zhang Q, Soman KV, Lau PP, Chan L (1999). "Mutational analysis of apolipoprotein B mRNA editing enzyme (APOBEC1). structure-function relationships of RNA editing and dimerization". J. Lipid Res. 40 (4): 623–35. doi: 10.1016/S0022-2275(20)32141-6 . PMID   10191286.
  8. ↑ Jarmuz A, Chester A, Bayliss J, Gisbourne J, Dunham I, Scott J, Navaratnam N (2002). "An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22". Genomics. 79 (3): 285–96. doi:10.1006/geno.2002.6718. PMID   11863358.
  9. ↑ Gee P, Ando Y, Kitayama H, Yamamoto SP, Kanemura Y, Ebina H, Kawaguchi Y, Koyanagi Y (2011). "APOBEC1-mediated editing and attenuation of herpes simplex virus 1 DNA indicate that neurons have an antiviral role during herpes simplex encephalitis". J. Virol. 85 (19): 9726–36. doi:10.1128/JVI.05288-11. PMC   3196441 . PMID   21775448.
  10. 1 2 3 4 5 Smith H (12 September 2008). "The APOBEC1 Paradigm for Mammalian Cytidine Deaminases That Edit DNA and RNA" (PDF). In Henri Grosjean (ed.). DNA and RNA Modification Enzymes: Comparative Structure, Mechanism, Functions, Cellular Interactions and Evolution. Landes Bioscience. Retrieved 24 February 2014.
  11. ↑ Yang Y, Ballatori N, Smith HC (2002). "Apolipoprotein B mRNA editing and the reduction in synthesis and secretion of the atherogenic risk factor, apolipoprotein B100 can be effectively targeted through TAT-mediated protein transduction". Mol. Pharmacol. 61 (2): 269–76. doi:10.1124/mol.61.2.269. PMID   11809850.
  12. ↑ Blanc V, Davidson NO (2011). "Mouse and other rodent models of C to U RNA editing". RNA and DNA Editing. Methods in Molecular Biology. Vol. 718. pp. 121–35. doi:10.1007/978-1-61779-018-8_7. ISBN   978-1-61779-017-1. PMC   3608419 . PMID   21370045.
  13. ↑ von Wronski MA, Hirano KI, Cagen LM, Wilcox HG, Raghow R, Thorngate FE, Heimberg M, Davidson NO, Elam MB (1998). "Insulin increases expression of apobec-1, the catalytic subunit of the apolipoprotein B mRNA editing complex in rat hepatocytes". Metab. Clin. Exp. 47 (7): 869–73. doi:10.1016/s0026-0495(98)90128-7. PMID   9667237.
  14. ↑ Yang Y, Sowden MP, Yang Y, Smith HC (2001). "Intracellular trafficking determinants in APOBEC-1, the catalytic subunit for cytidine to uridine editing of apolipoprotein B mRNA". Exp. Cell Res. 267 (2): 153–64. doi:10.1006/excr.2001.5255. PMID   11426934.
  15. ↑ MacGinnitie AJ, Anant S, Davidson NO (1995). "Mutagenesis of apobec-1, the catalytic subunit of the mammalian apolipoprotein B mRNA editing enzyme, reveals distinct domains that mediate cytosine nucleoside deaminase, RNA binding, and RNA editing activity". J. Biol. Chem. 270 (24): 14768–75. doi: 10.1074/jbc.270.24.14768 . PMID   7782343.
  16. ↑ Lehmann DM, Galloway CA, Sowden MP, Smith HC (2006). "Metabolic regulation of apoB mRNA editing is associated with phosphorylation of APOBEC-1 complementation factor". Nucleic Acids Res. 34 (11): 3299–308. doi:10.1093/nar/gkl417. PMC   1500872 . PMID   16820530.
  17. ↑ Nakamuta M, Chang BH, Zsigmond E, Kobayashi K, Lei H, Ishida BY, Oka K, Li E, Chan L (1996). "Complete phenotypic characterization of apobec-1 knockout mice with a wild-type genetic background and a human apolipoprotein B transgenic background, and restoration of apolipoprotein B mRNA editing by somatic gene transfer of Apobec-1". J. Biol. Chem. 271 (42): 25981–8. doi:10.1074/jbc.271.42.25981. PMID   8824235.
  18. ↑ Chen Z, Eggerman TL, Bocharov AV, Baranova IN, Vishnyakova TG, Csako G, Patterson AP (2010). "Hypermutation induced by APOBEC-1 overexpression can be eliminated". RNA. 16 (5): 1040–52. doi:10.1261/rna.1863010. PMC   2856876 . PMID   20348446.
  19. ↑ Gonzalez MC, Suspène R, Henry M, Guétard D, Wain-Hobson S, Vartanian JP (2009). "Human APOBEC1 cytidine deaminase edits HBV DNA". Retrovirology. 6: 96. doi:10.1186/1742-4690-6-96. PMC   2770521 . PMID   19843348.
  20. ↑ Niavarani, Ahmadreza; Shahrabi Farahani, Asieh; Sharafkhah, Maryam; Rassoulzadegan, Minoo (2018-01-13). "Pancancer analysis identifies prognostic high-APOBEC1 expression level implicated in cancer in-frame insertions and deletions". Carcinogenesis. 39 (3): 327–335. doi: 10.1093/carcin/bgy005 . ISSN   0143-3334. PMID   29346513.
  21. ↑ Mukhopadhyay D, Anant S, Lee RM, Kennedy S, Viskochil D, Davidson NO (2002). "C-->U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme". Am. J. Hum. Genet. 70 (1): 38–50. doi:10.1086/337952. PMC   384902 . PMID   11727199.
  22. ↑ Blanc V, Navaratnam N, Henderson JO, Anant S, Kennedy S, Jarmuz A, Scott J, Davidson NO (March 2001). "Identification of GRY-RBP as an apolipoprotein B RNA-binding protein that interacts with both apobec-1 and apobec-1 complementation factor to modulate C to U editing". J. Biol. Chem. 276 (13): 10272–83. doi: 10.1074/jbc.M006435200 . PMID   11134005.
  23. ↑ Mehta A, Kinter MT, Sherman NE, Driscoll DM (March 2000). "Molecular cloning of apobec-1 complementation factor, a novel RNA-binding protein involved in the editing of apolipoprotein B mRNA". Mol. Cell. Biol. 20 (5): 1846–54. doi:10.1128/MCB.20.5.1846-1854.2000. PMC   85365 . PMID   10669759.
  24. ↑ Lau PP, Chan L (Dec 2003). "Involvement of a chaperone regulator, Bcl2-associated athanogene-4, in apolipoprotein B mRNA editing". J. Biol. Chem. 278 (52): 52988–96. doi: 10.1074/jbc.M310153200 . PMID   14559896.
  25. ↑ Lau PP, Chang BH, Chan L (April 2001). "Two-hybrid cloning identifies an RNA-binding protein, GRY-RBP, as a component of apobec-1 editosome". Biochem. Biophys. Res. Commun. 282 (4): 977–83. doi:10.1006/bbrc.2001.4679. PMID   11352648.

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