The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization.
Deaminase activity mediated by the human APOBEC3 family of proteins contributes to genomic instability and cancer. APOBEC3A is by far the most active in this family and can cause rapid cell death when overexpressed, but in general how the activity of APOBEC3s is regulated on a molecular level is unclear. In this study, the biochemical and structural basis of APOBEC3A substrate binding and specificity is elucidated. We find that specific binding of single-stranded DNA is regulated by the cooperative dimerization of APOBEC3A. The crystal structure elucidates this homodimer as a symmetric domain swap of the N-terminal residues. This dimer interface provides insights into how cooperative protein-protein interactions may affect function in the APOBEC3 enzymes and provides a potential scaffold for strategies aimed at reducing their mutation load.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Markus-Frederik
MF
Bohn
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Shivender M D
SMD
Shandilya
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Tania V
TV
Silvas
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Ellen A
EA
Nalivaika
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA; Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.
Takahide
T
Kouno
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Brian A
BA
Kelch
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Sean P
SP
Ryder
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA.
Nese
N
Kurt-Yilmaz
Department of Pediatrics and Program in Molecular Medicine, University of Massachusetts Medical School Worcester, MA 01605, USA.
Mohan
M
Somasundaran
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, 364 Plantation Street, MA 01605, USA. Electronic address: celia.schiffer@umassmed.edu.
Celia A
CA
Schiffer
D001665:Binding Sites; D018360:Crystallography, X-Ray; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism
D004277:DNA, Single-Stranded; D011506:Proteins; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase; D015032:Zinc