BIROn - Birkbeck Institutional Research Online

    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.

    Full text not available from this repository.

    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

    Statistics

    Activity Overview
    6 month trend
    0Downloads
    6 month trend
    269Hits

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item