Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B

被引：0
作者：
Ke Shi
Özlem Demir
Michael A. Carpenter
Jeff Wagner
Kayo Kurahashi
Reuben S. Harris
Rommie E. Amaro
Hideki Aihara
机构：
[1] Molecular Biology and Biophysics,Department of Biochemistry
[2] University of Minnesota,Masonic Cancer Center
[3] University of Minnesota,Institute for Molecular Virology
[4] University of Minnesota,Department of Chemistry and Biochemistry
[5] University of California,Center for Genome Engineering
[6] University of Minnesota,Howard Hughes Medical Institute
[7] University of Minnesota,undefined
来源：
Scientific Reports | / 7卷
关键词：
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
引用
收藏
相关论文
共 119 条
  • [21] Xu L(2012)APOBEC3B and AID have similar nuclear import mechanisms J Mol Biol 419 131-9
  • [22] Yan S(2017)Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B Nat Struct Mol Biol 24 222-4284
  • [23] Carpenter MA(2010)APOBEC3 proteins mediate the clearance of foreign DNA from human cells Nat Struct Mol Biol 17 4274-85
  • [24] Shi K(2010)Quantitative profiling of the full Nucleic Acids Res 38 9474-66
  • [25] Carpenter MA(2009) mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction J Virol 83 27753-9
  • [26] Kurahashi K(2010)Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets J Biol Chem 285 9340-1799
  • [27] Harris RS(2017)Innate immune signaling induces high levels of TC-specific deaminase activity in primary monocyte-derived cells through expression of APOBEC3A isoforms Nat Commun 8 1787-59
  • [28] Aihara H(2015)Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity Nucleic Acids Res 43 2944-5613
  • [29] Siriwardena SU(2017)Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme J Mol Biol 429 5602-11
  • [30] Guruge TA(2016)Family-wide comparative analysis of cytidine and methylcytidine deamination by eleven human APOBEC proteins Biochemistry 55 903-304
12345678910