Changes in Apaf-1 conformation that drive apoptosome assembly.
Changes in Apaf-1 conformation that drive apoptosome assembly.
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DOI：
10.1021/bi301721g
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发表时间：
2013-04-02
期刊：
影响因子：
2.9
通讯作者：
Akey CW
中科院分区：
文献类型：
--
作者：
Yuan S;Topf M;Reubold TF;Eschenburg S;Akey CW
Apoptosome assembly is highly regulated in the intrinsic cell death pathway. To better understand this step, we created an improved model of the human apoptosome using a crystal structure of full length Apaf-1 and a single particle, electron density map at ~9.5Å resolution. The apoptosome model includes N-terminal domains of Apaf-1, cognate β-propellers and cytochrome c. A direct comparison of Apaf-1 in the apoptosome and as a monomer reveals conformational changes that occur during the first two steps of assembly. This includes an induced-fit mechanism for cytochrome c binding to regulatory β-propellers, which is dependent on shape and charge complimentarity, and a large rotation of the nucleotide binding module during nucleotide exchange. These linked conformational changes create an extended Apaf-1 monomer and drive apoptosome assembly. Moreover, the N-terminal CARD in the inactive Apaf-1 monomer is not shielded from other proteins by β–propellers. Hence, the Apaf-1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly. Irrespective of the timing, the end product of assembly is a holo-apoptosome with an acentric CARD-CARD disk and tethered pc-9 catalytic domains. Subsequent activation of pc-9 leads to a proteolytic cascade and cell death.
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