The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization.
The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization.
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DOI：
10.1016/j.str.2015.03.016
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发表时间：
2015-05-05
期刊：
影响因子：
--
通讯作者：
Schiffer CA
中科院分区：
文献类型：
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作者：
Bohn MF;Shandilya SMD;Silvas TV;Nalivaika EA;Kouno T;Kelch BA;Ryder SP;Kurt-Yilmaz N;Somasundaran M;Schiffer CA
人类APOBEC3蛋白家族介导的脱氨酶活性与基因组不稳定性和癌症有关。到目前为止，APOBEC3A是该家族中最活跃的，当过度表达时可导致细胞快速死亡，但总的来说，APOBEC3s的活性是如何在分子水平上调控的尚不清楚。本研究阐明了APOBEC3A底物结合和特异性的生化和结构基础。我们发现单链DNA的特异性结合是由APOBEC3A的合作二聚化调节的。晶体结构表明这种同型二聚体是n端残基的对称交换结构。这种二聚体界面提供了合作蛋白-蛋白相互作用如何影响APOBEC3酶功能的见解，并为旨在减少其突变负荷的策略提供了潜在的支架。人类APOBEC3A是一种强诱变的ssDNA单域胞嘧啶脱氨酶。Bohn等人证明，有效的协同结合发生在底物上，而失去了有效的产品释放。晶体结构显示为同二聚体，突变分析证实了协同性的必要性，为底物识别提供了模型。
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 homo-dimer as a symmetric domain swap of the N-terminal residues. This dimer interface provides insights into how cooperative protein-protein interactions may impact function in the APOBEC3 enzymes, and provides a potential scaffold for strategies aimed at reducing their mutation load. Human APOBEC3A is a strongly mutagenic ssDNA single domain cytosine deaminase. Bohn et al. demonstrate that potent cooperative binding occurs to substrate, while lost for efficient product release. The crystal structure revealed a homodimer, which mutational analysis confirmed is required for the cooperativity, providing a model for substrate recognition.