The APOBEC-2 crystal structure and functional implications for the deaminase AID
The APOBEC-2 crystal structure and functional implications for the deaminase AID
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DOI：
10.1038/nature05492
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发表时间：
2007-01-25
期刊：
影响因子：
64.8
通讯作者：
Chen, Xiaojiang S.
中科院分区：
文献类型：
--
作者：
Prochnow, Courtney;Bransteitter, Ronda;Chen, Xiaojiang S.
apobec2 （APO2）属于载脂蛋白B信使rna编辑酶催化（APOBEC）多肽家族，其作用是脱氨mRNA和单链DNA（1,2）。不同的APOBEC成员使用相同的脱氨活性来实现不同的人体生物学功能。被称为激活诱导胞苷脱氨酶（AID）的APOBEC蛋白的脱氨作用对于产生高亲和力抗体至关重要(3)，而apobec3蛋白的脱氨作用可以抑制逆转录转座子和逆转录病毒如人类免疫缺陷病毒和乙型肝炎病毒的复制（4-7）。本文报道了APO2的晶体结构。APO2形成一种杆状四聚体，与游离核苷酸胞苷脱氨酶的方形四聚体明显不同，apoobec蛋白与游离核苷酸胞苷脱氨酶具有相当大的序列同源性。在APO2中，单体结构的两个长α -螺旋阻止方形四聚体的形成，并通过两个APO2二聚体的头对头相互作用促进棒状四聚体的形成。apoobec家族成员之间广泛的序列同源性使我们能够使用AID测试基于APO2结构的预测。我们发现，预测干扰寡聚化和底物进入的突变会损害AID的脱氨活性。该结构提示了高igm -2综合征患者的突变如何使AID失活，从而导致抗体成熟缺陷。
APOBEC-2 (APO2) belongs to the family of apolipoprotein B messenger RNA-editing enzyme catalytic ( APOBEC) polypeptides, which deaminates mRNA and single-stranded DNA(1,2). Different APOBEC members use the same deamination activity to achieve diverse human biological functions. Deamination by an APOBEC protein called activation-induced cytidine deaminase ( AID) is critical for generating high-affinity antibodies(3), and deamination by APOBEC-3 proteins can inhibit retrotransposons and the replication of retroviruses such as human immunodeficiency virus and hepatitis B virus(4-7). Here we report the crystal structure of APO2. APO2 forms a rod-shaped tetramer that differs markedly from the square-shaped tetramer of the free nucleotide cytidine deaminase, with which APOBEC proteins share considerable sequence homology. In APO2, two long alpha-helices of a monomer structure prevent the formation of a square-shaped tetramer and facilitate formation of the rod-shaped tetramer via head-to-head interactions of two APO2 dimers. Extensive sequence homology among APOBEC family members allows us to test APO2 structure-based predictions using AID. We show that AID deamination activity is impaired by mutations predicted to interfere with oligomerization and substrate access. The structure suggests how mutations in patients with hyper-IgM-2 syndrome inactivate AID, resulting in defective antibody maturation.