Zinc Enhancement of Cytidine Deaminase Activity Highlights a Potential Allosteric Role of Loop-3 in Regulating APOBEC3 Enzymes

Overview

Journal Sci Rep

Specialty Science

Date 2015 Dec 19

PMID 26678087

Citations 10

Authors

Ailie Marx

Meytal Galilee

Akram Alian

Affiliations

Soon will be listed here.

Abstract

The strong association of APOBEC3 cytidine deaminases with somatic mutations leading to cancers accentuates the importance of their tight intracellular regulation to minimize cellular transformations. We reveal a novel allosteric regulatory mechanism of APOBEC3 enzymes showing that APOBEC3G and APOBEC3A coordination of a secondary zinc ion, reminiscent to ancestral deoxycytidylate deaminases, enhances deamination activity. Zinc binding is pinpointed to loop-3 which whilst highly variable harbors a catalytically essential and spatially conserved asparagine at its N-terminus. We suggest that loop-3 may play a general role in allosterically tuning the activity of zinc-dependent cytidine deaminase family members.

Citing Articles

Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination.

Pecori R, Di Giorgio S, Lorenzo J, Papavasiliou F Nat Rev Genet. 2022; 23(8):505-518.

PMID: 35256818 PMC: 8900473. DOI: 10.1038/s41576-022-00459-8.

Structure-Based Design of First-Generation Small Molecule Inhibitors Targeting the Catalytic Pockets of AID, APOBEC3A, and APOBEC3B.

King J, Borzooee F, Im J, Asgharpour M, Ghorbani A, Diamond C ACS Pharmacol Transl Sci. 2021; 4(4):1390-1407.

PMID: 34423273 PMC: 8369683. DOI: 10.1021/acsptsci.1c00091.

The Role of APOBECs in Viral Replication.

Xu W, Byun H, Dudley J Microorganisms. 2020; 8(12).

PMID: 33266042 PMC: 7760323. DOI: 10.3390/microorganisms8121899.

Structural Insights into APOBEC3-Mediated Lentiviral Restriction.

Delviks-Frankenberry K, Desimmie B, Pathak V Viruses. 2020; 12(6).

PMID: 32471198 PMC: 7354603. DOI: 10.3390/v12060587.

Diversification of AID/APOBEC-like deaminases in metazoa: multiplicity of clades and widespread roles in immunity.

Krishnan A, Iyer L, Holland S, Boehm T, Aravind L Proc Natl Acad Sci U S A. 2018; 115(14):E3201-E3210.

PMID: 29555751 PMC: 5889660. DOI: 10.1073/pnas.1720897115.

References

Kitamura S, Ode H, Nakashima M, Imahashi M, Naganawa Y, Kurosawa T . The APOBEC3C crystal structure and the interface for HIV-1 Vif binding. Nat Struct Mol Biol. 2012; 19(10):1005-10. DOI: 10.1038/nsmb.2378. View

Logue E, Bloch N, Dhuey E, Zhang R, Cao P, Herate C . A DNA sequence recognition loop on APOBEC3A controls substrate specificity. PLoS One. 2014; 9(5):e97062. PMC: 4020817. DOI: 10.1371/journal.pone.0097062. View

Britan-Rosich E, Nowarski R, Kotler M . Multifaceted counter-APOBEC3G mechanisms employed by HIV-1 Vif. J Mol Biol. 2011; 410(5):1065-76. PMC: 3139112. DOI: 10.1016/j.jmb.2011.03.058. View

Bohn M, Shandilya S, Albin J, Kouno T, Anderson B, McDougle R . Crystal structure of the DNA cytosine deaminase APOBEC3F: the catalytically active and HIV-1 Vif-binding domain. Structure. 2013; 21(6):1042-50. PMC: 3805256. DOI: 10.1016/j.str.2013.04.010. View

Kohli R, Abrams S, Gajula K, Maul R, Gearhart P, Stivers J . A portable hot spot recognition loop transfers sequence preferences from APOBEC family members to activation-induced cytidine deaminase. J Biol Chem. 2009; 284(34):22898-904. PMC: 2755697. DOI: 10.1074/jbc.M109.025536. View

Conticello S . The AID/APOBEC family of nucleic acid mutators. Genome Biol. 2008; 9(6):229. PMC: 2481415. DOI: 10.1186/gb-2008-9-6-229. View

Kouno T, Luengas E, Shigematsu M, Shandilya S, Zhang J, Chen L . Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G. Nat Struct Mol Biol. 2015; 22(6):485-91. PMC: 4456288. DOI: 10.1038/nsmb.3033. View

Notredame C, Higgins D, Heringa J . T-Coffee: A novel method for fast and accurate multiple sequence alignment. J Mol Biol. 2000; 302(1):205-17. DOI: 10.1006/jmbi.2000.4042. View

Laitaoja M, Valjakka J, Janis J . Zinc coordination spheres in protein structures. Inorg Chem. 2013; 52(19):10983-91. DOI: 10.1021/ic401072d. View

10.

Siu K, Sultana A, Azimi F, Lee J . Structural determinants of HIV-1 Vif susceptibility and DNA binding in APOBEC3F. Nat Commun. 2013; 4:2593. PMC: 4956467. DOI: 10.1038/ncomms3593. View

11.

Dang Y, Abudu A, Son S, Harjes E, Spearman P, Matsuo H . Identification of a single amino acid required for APOBEC3 antiretroviral cytidine deaminase activity. J Virol. 2011; 85(11):5691-5. PMC: 3094948. DOI: 10.1128/JVI.00243-11. View

12.

Vasudevan A, Smits S, Hoppner A, Haussinger D, Koenig B, Munk C . Structural features of antiviral DNA cytidine deaminases. Biol Chem. 2013; 394(11):1357-70. DOI: 10.1515/hsz-2013-0165. View

13.

Swanton C, McGranahan N, Starrett G, Harris R . APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity. Cancer Discov. 2015; 5(7):704-12. PMC: 4497973. DOI: 10.1158/2159-8290.CD-15-0344. View

14.

Byeon I, Ahn J, Mitra M, Byeon C, Hercik K, Hritz J . NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity. Nat Commun. 2013; 4:1890. PMC: 3674325. DOI: 10.1038/ncomms2883. View

15.

Holden L, Prochnow C, Chang Y, Bransteitter R, Chelico L, Sen U . Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications. Nature. 2008; 456(7218):121-4. PMC: 2714533. DOI: 10.1038/nature07357. View

16.

Conticello S, Langlois M, Yang Z, Neuberger M . DNA deamination in immunity: AID in the context of its APOBEC relatives. Adv Immunol. 2007; 94:37-73. DOI: 10.1016/S0065-2776(06)94002-4. View

17.

Nowarski R, Britan-Rosich E, Shiloach T, Kotler M . Hypermutation by intersegmental transfer of APOBEC3G cytidine deaminase. Nat Struct Mol Biol. 2008; 15(10):1059-66. DOI: 10.1038/nsmb.1495. View

18.

Rebhandl S, Huemer M, Greil R, Geisberger R . AID/APOBEC deaminases and cancer. Oncoscience. 2015; 2(4):320-33. PMC: 4468319. DOI: 10.18632/oncoscience.155. View

19.

Chen K, Martemyanova N, Lu Y, Shindo K, Matsuo H, Harris R . Extensive mutagenesis experiments corroborate a structural model for the DNA deaminase domain of APOBEC3G. FEBS Lett. 2007; 581(24):4761-6. PMC: 2014798. DOI: 10.1016/j.febslet.2007.08.076. View

20.

Refsland E, Harris R . The APOBEC3 family of retroelement restriction factors. Curr Top Microbiol Immunol. 2013; 371:1-27. PMC: 3934647. DOI: 10.1007/978-3-642-37765-5_1. View