University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology; Program in Molecular Medicine; Schiffer Lab
Publication Date
2017-04-28
Document Type
Article
Disciplines
Biochemistry | Enzymes and Coenzymes | Molecular Biology | Structural Biology
Abstract
Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active site poised for catalysis of APOBEC3A, but pinpoints the residues that confer specificity towards CC/TC motifs. The APOBEC3A-ssDNA complex defines the 5'-3' directionality and subtle conformational changes that clench the ssDNA within the binding groove, revealing the architecture and mechanism of ssDNA recognition that is likely conserved among all polynucleotide deaminases, thereby opening the door for the design of mechanistic-based therapeutics.
Keywords
APOBEC3A, crystal structure, cytidine deaminase
Rights and Permissions
Copyright The Author(s) 2017.
DOI of Published Version
10.1038/ncomms15024
Source
Nat Commun. 2017 Apr 28;8:15024. doi: 10.1038/ncomms15024. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Nature communications
PubMed ID
28452355
Repository Citation
Kouno, Takahide; Silvas, Tania V.; Hilbert, Brendan J.; Shandilya, Shivender; Bohn, Markus-Frederik; Kelch, Brian A.; Royer, William E.; Somasundaran, Mohan; Yilmaz, Nese Kurt; Matsuo, Hiroshi; and Schiffer, Celia A., "Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity" (2017). University of Massachusetts Medical School Faculty Publications. 1356.
https://escholarship.umassmed.edu/faculty_pubs/1356
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