The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization

被引：73

作者：

Bohn, Markus-Frederik ^{[1
]}

Shandilya, Shivender M. D. ^{[1
]}

Silvas, Tania V. ^{[1
]}

Nalivaika, Ellen A. ^{[1
]}

Kouno, Takahide ^{[1
,2
]}

Kelch, Brian A. ^{[1
]}

Ryder, Sean P. ^{[1
]}

Kurt-Yilmaz, Nese ^{[1
]}

Somasundaran, Mohan ^{[3
,4
]}

Schiffer, Celia A. ^{[1
]}

机构：

[1] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA

[2] Univ Minnesota, Inst Mol Virol, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA

[3] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA

[4] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA

来源：

STRUCTURE | 2015年 / 23卷 / 05期

关键词：

TRANSITION-STATE ANALOG; CYTIDINE DEAMINASE; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; STRUCTURAL DETERMINANTS; ANTIRETROVIRAL FACTOR; BIOCHEMICAL-ANALYSIS; HIV-1; RESTRICTION; DNA DEMETHYLATION; FOREIGN DNA;

D O I：

10.1016/j.str.2015.03.016

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：903 / 911

页数：9

共 76 条

[1]

Different Mutagenic Potential of HIV-1 Restriction Factors APOBEC3G and APOBEC3F Is Determined by Distinct Single-Stranded DNA Scanning Mechanisms [J].