Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B

Shi, Ke; Demir, Özlem; Carpenter, Michael A.; Wagner, Jeff; Kurahashi, Kayo; Harris, Reuben S.; Amaro, Rommie E.; Aihara, Hideki

doi:10.1038/s41598-017-17694-3

Title: Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B

Journal Article · Tue Dec 12 00:00:00 EST 2017 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-017-17694-3· OSTI ID:1430344

Shi, Ke ^[1]; Demir, Özlem ^[2]; Carpenter, Michael A. ^[1]; Wagner, Jeff ^[2]; Kurahashi, Kayo ^[1]; Harris, Reuben S. ^[1];

^[2]; Aihara, Hideki ^[1]

Univ. of Minnesota, Minneapolis, MN (United States)
Univ. of California, San Diego, La Jolla, CA (United States)

The APOBEC3B (A3B) single-stranded DNA (ssDNA) cytosine deaminase has important roles in innate immunity but is also a major endogenous source of mutations in cancer. Previous structural studies showed that the C-terminal catalytic domain of human A3B has a tightly closed active site, and rearrangement of the surrounding loops is required for binding to substrate ssDNA. Here we report structures of the A3B catalytic domain in a new crystal form that show alternative, yet still closed, conformations of active site loops. All-atom molecular dynamics simulations support the dynamic behavior of active site loops and recapitulate the distinct modes of interactions that maintain a closed active site. Replacing segments of A3B loop 1 to mimic the more potent cytoplasmic deaminase APOBEC3A leads to elevated ssDNA deaminase activity, likely by facilitating opening of the active site. These data collectively suggest that conformational equilibrium of the A3B active site loops, skewed toward being closed, controls enzymatic activity by regulating binding to ssDNA substrates.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; US National Inst. of Health; National Science Foundation (NSF); NIH-ORIP HEI

Grant/Contract Number:: AC02-06CH11357; NIGMS R01-GM118000; S10 RR029205; NIGMS R35-GM118047; R21-CA206309; DP2-OD007237; NIGMS P41-GM103426; CHE060073N; NIGMS P41-GM103403

OSTI ID:: 1430344

Journal Information:: Scientific Reports, Vol. 7, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 19 works

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References (61)

Methylcytosine and Normal Cytosine Deamination by the Foreign DNA Restriction Enzyme APOBEC3A Carpenter, Michael A.; Li, Ming; Rathore, Anurag Journal of Biological Chemistry, Vol. 287, Issue 41 https://doi.org/10.1074/jbc.M112.385161	journal	August 2012
The Role of Amino-Terminal Sequences in Cellular Localization and Antiviral Activity of APOBEC3B Pak, V.; Heidecker, G.; Pathak, V. K. Journal of Virology, Vol. 85, Issue 17 https://doi.org/10.1128/JVI.02645-10	journal	June 2011
Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation Xiao, Xiao; Yang, Hanjing; Arutiunian, Vagan Nucleic Acids Research, Vol. 45, Issue 12 https://doi.org/10.1093/nar/gkx564	journal	June 2017
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
A Biochemical Analysis Linking APOBEC3A to Disparate HIV-1 Restriction and Skin Cancer Pham, Phuong; Landolph, Alice; Mendez, Carlos Journal of Biological Chemistry, Vol. 288, Issue 41 https://doi.org/10.1074/jbc.m113.504175	journal	August 2013
A computational analysis of the structural determinants of APOBEC3’s catalytic activity and vulnerability to HIV-1 Vif Shandilya, Shivender M. D.; Bohn, Markus-Frederik; Schiffer, Celia A. Virology, Vol. 471-473 https://doi.org/10.1016/j.virol.2014.09.023	journal	December 2014
Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction Refsland, Eric W.; Stenglein, Mark D.; Shindo, Keisuke Nucleic Acids Research, Vol. 38, Issue 13 https://doi.org/10.1093/nar/gkq174	journal	March 2010
The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization Bohn, Markus-Frederik; Shandilya, Shivender M. D.; Silvas, Tania V. Structure, Vol. 23, Issue 5 https://doi.org/10.1016/j.str.2015.03.016	journal	May 2015
Hypermutation in human cancer genomes: footprints and mechanisms Roberts, Steven A.; Gordenin, Dmitry A. Nature Reviews Cancer, Vol. 14, Issue 12 https://doi.org/10.1038/nrc3816	journal	November 2014
Two Regions within the Amino-Terminal Half of APOBEC3G Cooperate To Determine Cytoplasmic Localization Stenglein, M. D.; Matsuo, H.; Harris, R. S. Journal of Virology, Vol. 82, Issue 19 https://doi.org/10.1128/JVI.02471-07	journal	July 2008
Graphical analysis of pH-dependent properties of proteins predicted using PROPKA Rostkowski, Michał; Olsson, Mats HM; Søndergaard, Chresten R. BMC Structural Biology, Vol. 11, Issue 1 https://doi.org/10.1186/1472-6807-11-6	journal	January 2011
APOBEC3 proteins mediate the clearance of foreign DNA from human cells Stenglein, Mark D.; Burns, Michael B.; Li, Ming Nature Structural & Molecular Biology, Vol. 17, Issue 2 https://doi.org/10.1038/nsmb.1744	journal	January 2010
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer Law, Emily K.; Sieuwerts, Anieta M.; LaPara, Kelly Science Advances, Vol. 2, Issue 10 https://doi.org/10.1126/sciadv.1601737	journal	October 2016
APOBEC3B and APOBEC3F Inhibit L1 Retrotransposition by a DNA Deamination-independent Mechanism Stenglein, Mark D.; Harris, Reuben S. Journal of Biological Chemistry, Vol. 281, Issue 25 https://doi.org/10.1074/jbc.m602367200	journal	April 2006
Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B Shi, Ke; Carpenter, Michael A.; Banerjee, Surajit Nature Structural & Molecular Biology, Vol. 24, Issue 2 https://doi.org/10.1038/nsmb.3344	journal	December 2016
Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme Caval, Vincent; Bouzidi, Mohamed S.; Suspène, Rodolphe Nucleic Acids Research, Vol. 43, Issue 19 https://doi.org/10.1093/nar/gkv935	journal	September 2015
Cellular inhibitors of long interspersed element 1 and Alu retrotransposition Bogerd, H. P.; Wiegand, H. L.; Hulme, A. E. Proceedings of the National Academy of Sciences, Vol. 103, Issue 23 https://doi.org/10.1073/pnas.0603313103	journal	May 2006
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Novel Zinc Protein Molecular Dynamics Simulations: Steps Toward Antiangiogenesis for Cancer Treatment Pang, Yuan-Ping Journal of Molecular Modeling, Vol. 5, Issue 10 https://doi.org/10.1007/s008940050119	journal	October 1999
APOBECs and virus restriction Harris, Reuben S.; Dudley, Jaquelin P. Virology, Vol. 479-480 https://doi.org/10.1016/j.virol.2015.03.012	journal	May 2015
Increased APOBEC3B Predicts Worse Outcomes in Lung Cancer: A Comprehensive Retrospective Study Yan, Shumei; He, Fan; Gao, Bei Journal of Cancer, Vol. 7, Issue 6 https://doi.org/10.7150/jca.14030	journal	January 2016
APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity Swanton, C.; McGranahan, N.; Starrett, G. J. Cancer Discovery, Vol. 5, Issue 7 https://doi.org/10.1158/2159-8290.cd-15-0344	journal	June 2015
POVME: An algorithm for measuring binding-pocket volumes Durrant, Jacob D.; de Oliveira, César Augusto F.; McCammon, J. Andrew Journal of Molecular Graphics and Modelling, Vol. 29, Issue 5 https://doi.org/10.1016/j.jmgm.2010.10.007	journal	February 2011
Intrinsic host restrictions to HIV-1 and mechanisms of viral escape Simon, Viviana; Bloch, Nicolin; Landau, Nathaniel R. Nature Immunology, Vol. 16, Issue 6 https://doi.org/10.1038/ni.3156	journal	May 2015
POVME 2.0: An Enhanced Tool for Determining Pocket Shape and Volume Characteristics Durrant, Jacob D.; Votapka, Lane; Sørensen, Jesper Journal of Chemical Theory and Computation, Vol. 10, Issue 11 https://doi.org/10.1021/ct500381c	journal	October 2014
Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins Ito, Fumiaki; Fu, Yang; Kao, Shen-Chi A. Journal of Molecular Biology, Vol. 429, Issue 12 https://doi.org/10.1016/j.jmb.2017.04.021	journal	June 2017
Mechanisms underlying mutational signatures in human cancers Helleday, Thomas; Eshtad, Saeed; Nik-Zainal, Serena Nature Reviews Genetics, Vol. 15, Issue 9 https://doi.org/10.1038/nrg3729	journal	July 2014
Defining APOBEC3 Expression Patterns in Human Tissues and Hematopoietic Cell Subsets Koning, F. A.; Newman, E. N. C.; Kim, E. -Y. Journal of Virology, Vol. 83, Issue 18 https://doi.org/10.1128/jvi.01089-09	journal	July 2009
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00255	journal	July 2015
Impact of H216 on the DNA Binding and Catalytic Activities of the HIV Restriction Factor APOBEC3G Harjes, S.; Solomon, W. C.; Li, M. Journal of Virology, Vol. 87, Issue 12 https://doi.org/10.1128/jvi.03173-12	journal	April 2013
APOBEC3B and AID Have Similar Nuclear Import Mechanisms Lackey, Lela; Demorest, Zachary L.; Land, Allison M. Journal of Molecular Biology, Vol. 419, Issue 5 https://doi.org/10.1016/j.jmb.2012.03.011	journal	June 2012
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations Darden, Tom; Perera, Lalith; Li, Leping Structure, Vol. 7, Issue 3 https://doi.org/10.1016/s0969-2126(99)80033-1	journal	March 1999
Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity Byeon, In-Ja L.; Byeon, Chang-Hyeock; Wu, Tiyun Biochemistry, Vol. 55, Issue 21 https://doi.org/10.1021/acs.biochem.6b00382	journal	May 2016
APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma Walker, Brian A.; Wardell, Christopher P.; Murison, Alex Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms7997	journal	April 2015
Elevated APOBEC3B Correlates with Poor Outcomes for Estrogen-Receptor-Positive Breast Cancers Sieuwerts, Anieta M.; Willis, Scooter; Burns, Michael B. Hormones and Cancer, Vol. 5, Issue 6 https://doi.org/10.1007/s12672-014-0196-8	journal	August 2014
Mechanism of high-mannose N-glycan breakdown and metabolism by Bifidobacterium longum Cordeiro, Rosa L.; Santos, Camila R.; Domingues, Mariane N. Nature Chemical Biology, Vol. 19, Issue 2 https://doi.org/10.1038/s41589-022-01202-4	journal	November 2022
Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms Thielen, Beth K.; McNevin, John P.; McElrath, M. Juliana Journal of Biological Chemistry, Vol. 285, Issue 36 https://doi.org/10.1074/jbc.m110.102822	journal	July 2010
APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation Cescon, David W.; Haibe-Kains, Benjamin; Mak, Tak W. Proceedings of the National Academy of Sciences, Vol. 112, Issue 9 https://doi.org/10.1073/pnas.1424869112	journal	February 2015
DNA cytosine and methylcytosine deamination by APOBEC3B: enhancing methylcytosine deamination by engineering APOBEC3B Fu, Yang; Ito, Fumiaki; Zhang, Gewen Biochemical Journal, Vol. 471, Issue 1 https://doi.org/10.1042/bj20150382	journal	September 2015
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
POVME 3.0: Software for Mapping Binding Pocket Flexibility Wagner, Jeffrey R.; Sørensen, Jesper; Hensley, Nathan Journal of Chemical Theory and Computation, Vol. 13, Issue 9 https://doi.org/10.1021/acs.jctc.7b00500	journal	August 2017
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data Roe, Daniel R.; Cheatham, Thomas E. Journal of Chemical Theory and Computation, Vol. 9, Issue 7 https://doi.org/10.1021/ct400341p	journal	June 2013
APOBEC3B high expression status is associated with aggressive phenotype in Japanese breast cancers Tsuboi, Miki; Yamane, Arito; Horiguchi, Jun Breast Cancer, Vol. 23, Issue 5 https://doi.org/10.1007/s12282-015-0641-8	journal	October 2015
Spontaneous drying of non-polar deep-cavity cavitand pockets in aqueous solution Barnett, J. Wesley; Sullivan, Matthew R.; Long, Joshua A. Nature Chemistry, Vol. 12, Issue 7 https://doi.org/10.1038/s41557-020-0458-8	journal	May 2020
Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation Xiao, Xiao; Yang, Hanjing; Arutiunian, Vagan Nucleic Acids Research, Vol. 45, Issue 12 https://doi.org/10.1093/nar/gkx362	journal	May 2017
Crystal structures of APOBEC3G N-domain alone and its complex with DNA Xiao, Xiao; Li, Shu-Xing; Yang, Hanjing Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms12193	journal	August 2016
Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity Kouno, Takahide; Silvas, Tania V.; Hilbert, Brendan J. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms15024	journal	April 2017
NMR-based method of small changes reveals how DNA mutator APOBEC3A interacts with its single-stranded DNA substrate Harjes, Stefan; Jameson, Geoffrey B.; Filichev, Vyacheslav V. Nucleic Acids Research, Vol. 45, Issue 9 https://doi.org/10.1093/nar/gkx196	journal	March 2017
Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain Shi, Ke; Carpenter, Michael A.; Kurahashi, Kayo Journal of Biological Chemistry, Vol. 290, Issue 47 https://doi.org/10.1074/jbc.M115.679951	journal	September 2015
Structural basis for directional chitin biosynthesis Chen, Wei; Cao, Peng; Liu, Yuansheng Nature, Vol. 610, Issue 7931 https://doi.org/10.1038/s41586-022-05244-5	journal	September 2022
Functions and Malfunctions of Mammalian DNA-Cytosine Deaminases Siriwardena, Sachini U.; Chen, Kang; Bhagwat, Ashok S. Chemical Reviews, Vol. 116, Issue 20 https://doi.org/10.1021/acs.chemrev.6b00296	journal	May 2016
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-13641-0	journal	December 2019
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity Byeon, In-Ja L.; Ahn, Jinwoo; Mitra, Mithun Nature Communications, Vol. 4, Issue 1 https://doi.org/10.1038/ncomms2883	journal	May 2013
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations Tom, Darden,; Lee, Pedersen,; Leping, Li, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/xp7j-h168	text	January 1999
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models Miyamoto, Shuichi; Kollman, Peter A. Journal of Computational Chemistry, Vol. 13, Issue 8 https://doi.org/10.1002/jcc.540130805	journal	October 1992
Characterization of the Catalytic Domain of Human APOBEC3B and the Critical Structural Role for a Conserved Methionine Siriwardena, Sachini U.; Guruge, Thisari A.; Bhagwat, Ashok S. Journal of Molecular Biology, Vol. 427, Issue 19 https://doi.org/10.1016/j.jmb.2015.08.006	journal	September 2015
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007

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