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Title | Changes in Apaf-1 conformation that drive apoptosome assembly. |
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Journal, issue, pages | Biochemistry, Vol. 52, Issue 13, Page 2319-2327, Year 2013 |
Publish date | Apr 2, 2013 |
Authors | Shujun Yuan / Maya Topf / Thomas F Reubold / Susanne Eschenburg / Christopher W Akey / |
PubMed 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 ...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. |
External links | Biochemistry / PubMed:23521171 / PubMed Central |
Methods | EM (single particle) |
Resolution | 9.5 Å |
Structure data | PDB-3j2t: |
Chemicals | ChemComp-ATP: ChemComp-HEM: |
Source |
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Keywords | APOPTOSIS / Apoptosis protease activating factor-1 / Apaf-1 / cytochrome c |