Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B

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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
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Scientific Reports | / 7卷
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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.
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