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    Changes in Apaf-1 conformation that drive apoptosome assembly

    Yuan, Shujun and Topf, Maya and Reubold, T.F. and Eschenburg, S. and Akey, C.W. (2013) Changes in Apaf-1 conformation that drive apoptosome assembly. Biochemistry 52 (13), pp. 2319-2327. ISSN 0006-2960.

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    Abstract

    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 ∼9.5 Å 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 complementarity, 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.

    Metadata

    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Bioinformatics, Bloomsbury Centre for (Closed), Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 11 May 2015 14:24
    Last Modified: 02 Aug 2023 17:16
    URI: https://eprints.bbk.ac.uk/id/eprint/12025

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