APOBEC

{{short description|Enzyme involved in messenger RNA editing}} [[image:Apobec.J.Steinfeld.D.png|300px|thumb|upright|'''Example of a member of the APOBEC family, APOBEC-2'''. A cytidine deaminase from ''Homo sapiens''.<ref name="Prochnow1">{{PDB|2NYT}}; {{cite journal | vauthors = Prochnow C, Bransteitter R, Klein MG, Goodman MF, Chen XS | title = The APOBEC-2 crystal structure and functional implications for the deaminase AID | journal = Nature | volume = 445 | issue = 7126 | pages = 447–451 | date = January 2007 | pmid = 17187054 | doi = 10.1038/nature05492 | s2cid = 4394772 | bibcode = 2007Natur.445..447P }}; rendered using [http://pymol.sourceforge.net PyMOL].</ref>]] {{Infobox protein family | Symbol = APOBEC_N | Name = APOBEC-like N-terminal domain | image = | width = | caption = | Pfam= PF08210 | InterPro= IPR013158 | SMART= | Prosite = | SCOP = | TCDB = | OPM family= | OPM protein= | PDB= }} {{Pfam_box | Symbol = APOBEC_C | Name = APOBEC-like C-terminal domain | image = | width = | caption = | Pfam= PF05240 | InterPro= IPR007904 | SMART= | Prosite = | SCOP = | TCDB = | OPM family= | OPM protein= | PDB= }} '''APOBEC''' ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide") is a family of evolutionarily conserved [[cytidine deaminase]]s.

== Function ==

A mechanism of generating protein diversity is [[messenger RNA|mRNA]] editing. The APOBEC family of proteins perform mRNA modifications by deaminating cytidine bases to uracil. The [[N-terminus|N-terminal]] domain of APOBEC-like proteins is the catalytic domain, while the [[C-terminus|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]].<ref name="pmid12683974">{{cite journal | vauthors = Wedekind JE, Dance GS, Sowden MP, Smith HC | title = Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business | journal = Trends in Genetics | volume = 19 | issue = 4 | pages = 207–216 | date = April 2003 | pmid = 12683974 | doi = 10.1016/S0168-9525(03)00054-4 }}</ref> 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]].<ref>{{cite web|url=https://www.omim.org/entry/600130|title=APOLIPOPROTEIN B mRNA-EDITING ENZYME, CATALYTIC POLYPEPTIDE 1; APOBEC1|website=Online Mendelian Inheritance in Man|vauthors=McKusick VA, Hamosh A|date=19 December 2019|orig-date=Originally published 27 September 1994|access-date=23 December 2023}}</ref> For other APOBEC-modified transcripts such as in the site-specific deamination of a CGA to a UGA stop codon in neurofibromatosis type 1 (''[[Neurofibromin 1|NF1]]'') mRNA, the resulting proteins are predicted to be truncated as well, although these transcripts are possibly degraded.<ref>{{cite journal | vauthors = Blanc V, Davidson NO | title = C-to-U RNA editing: mechanisms leading to genetic diversity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 3 | pages = 1395–1398 | date = January 2003 | pmid = 12446660 | doi = 10.1074/jbc.r200024200 | doi-access = free }}</ref>

C-to-U modifications do not always result in the truncation of proteins. For example, in humans/mammals they help protect from viral infections.<ref name="APOBEC3-2016" /><ref name="pmid34353635">{{cite journal | vauthors = Cervantes-Gracia K, Gramalla-Schmitz A, Weischedel J, Chahwan R | title = APOBECs orchestrate genomic and epigenomic editing across health and disease | journal = Trends in Genetics | volume = 37 | issue = 11 | pages = 1028–1043 | date = November 2021 | pmid = 34353635 | doi = 10.1016/j.tig.2021.07.003 | s2cid = 236934922 | doi-access = free }}</ref> APOBEC family proteins are widely expressed in cells of the human innate immune system.<ref>{{cite journal | vauthors = Koito A, Ikeda T | title = Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases | journal = Frontiers in Microbiology | volume = 4 | pages = 28 | date = 2013 | pmid = 23431045 | pmc = 3576619 | doi = 10.3389/fmicb.2013.00028 | doi-access = free }}</ref>

== Cancer ==

These enzymes, when misregulated, are a major source of mutation in numerous cancer types.<ref name="APOBEC3-2016">{{cite web |url=http://www.genengnews.com/gen-news-highlights/unexpected-dna-binding-mechanism-suggests-ways-to-block-enzyme-activity-in-cancer/81253584 |title=''Unexpected DNA-Binding Mechanism Suggests Ways to Block Enzyme Activity in Cancer'' |date=Dec 2016 |quote=Based on ("Structural Basis for Targeted DNA Cytosine Deamination and Mutagenesis by APOBEC3A and APOBEC3B") online in Nature Structural and Molecular Biology. }}</ref><ref name="pmid34353635" /><ref>{{cite journal | vauthors = Butler K, Banday AR | title = APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential | journal = Journal of Hematology & Oncology | volume = 16 | issue = 1 | article-number = 31 | date = March 2023 | pmid = 36978147 | pmc = 10044795 | doi = 10.1186/s13045-023-01425-5 | doi-access = free }}</ref> 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.<ref>{{cite book | vauthors = Okazaki IM, Kotani A, Honjo T | title = AID for Immunoglobulin Diversity | chapter = Role of AID in tumorigenesis | series = Advances in Immunology | volume = 94 | pages = 245–273 | date = 2007-01-01 | pmid = 17560277 | doi = 10.1016/s0065-2776(06)94008-5 | publisher = Academic Press | isbn = 9780123737069 }}</ref>

== Structure ==

A 2013 review discussed the structural and biophysical aspects of APOBEC3 family enzymes.<ref>{{cite journal | vauthors = Vasudevan AA, Smits SH, Höppner A, Häussinger D, Koenig BW, Münk C | title = Structural features of antiviral DNA cytidine deaminases | journal = Biological Chemistry | volume = 394 | issue = 11 | pages = 1357–1370 | date = November 2013 | pmid = 23787464 | doi = 10.1515/hsz-2013-0165 | s2cid = 4151961 | url = http://juser.fz-juelich.de/record/139785/files/FZJ-2013-05757.pdf }}</ref> Many of the APOBEC protein features are described in the widely studied [[APOBEC3G]]'s page.{{tone inline|date=June 2022}}

==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 == {{Reflist}}

==Bibliography== *Gupta, A., Gazzo, A., Selenica, P. et al., ''APOBEC3 mutagenesis drives therapy resistance in breast cancer'', ''Nature Genetics'' (April 1, 2025) {{doi|10.1038/s41588-025-02187-1}}

[[Category:EC 3.5.4]]