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1.
Figure 6

Figure 6. The role of sensor I in Apaf-1 monomer and CED4 apoptosomes. From: Apoptosome structure, assembly and procaspase activation.

A. An icon view is shown of the Apaf-1 monomer.
B. Stabilizing interactions of sensor I (R265) with an acidic triangle of carboxylate groups in the inactive Apaf-1 monomer are shown (see inset). Note the distal position of the HD1-WHD loop.
C. An icon view is shown of a CED4 monomer extracted from the assembled apoptosome.
D. Sensor I (R273) interactions are shown with the γ-phosphate of ATP in the CED-4 apoptosome. The HD1-WHD loop is in close proximity to the ribose of ATP.

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.
2.
Figure 7

Figure 7. From: Apoptosome structure, assembly and procaspase activation.

Possible conformational changes that occur during Apaf-1 assembly are shown with inactive and active conformations aligned on the NBD. Cytochrome c binding may trigger inter-domain rearrangements and motions that lead to nucleotide exchange. An extensive rearrangement of the NBD-HD1 module occurs relative to the rest of Apaf-1. This creates an extended and assembly competent conformation. Procaspase-9 may interact with the CARD in the Apaf-1 monomer during nucleotide exchange leading directly to the formation of a CARD-CARD disk as the platform assembles.

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.
4.
Figure 2

Figure 2. Domain architecture and structures of Apaf-1 like proteins in the NOD super-family. From: Apoptosome structure, assembly and procaspase activation.

A. Linear domain representations are shown for CED-4, Apaf-1 and Dark. This domain color scheme is used throughout.
B. A crystal structure is shown of the CED-9 inhibited CED-4 lateral dimer (2A5Y). The CARD in monomer B is disordered (Yan et al., 2005) and the boundary between monomers is indicated by a dashed line.
C. A composite model is shown for an inactive Apaf-1 monomer based on two crystal structures (Reidl et al., 2005; Reubold et al., 2011).

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.
5.
Figure 8

Figure 8. Models of procaspase-9 activation on the human apoptosome. From: Apoptosome structure, assembly and procaspase activation.

A. A composite model is shown for the holo-apoptosome, based on cryo-EM structures for the platform and active complex (Yuan et al. submitted).
B. The platform is shown in grey and domains of pc-9 are color coded in a cartoon model of pc-9 activation. (top right) A proximity-induced dimerization model is shown with flexibly tethered pc-9 molecules. (bottom right) The proximity-induced association/allosteric model is shown. One p20-p10 catalytic domain (in gold) is bound to the hub and a possible second catalytic domain is shown as a dashed white oval, to indicate that it may be disordered.

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.
6.
Figure 4

Figure 4. Assembly models for ground state apoptosomes in worms, humans and flies. From: Apoptosome structure, assembly and procaspase activation.

A. CED-4 molecules in lateral dimers contain bound ATP and may represent an assembly intermediate blocked by CED-9 (Yan et al., 2005; Qi et al., 2010). EGL-1 interacts with CED-9 to promote further oligomerization of CED-4 to form the apoptosome.
B. Inactive Apaf-1 monomers (Reidl et al. 2005; Reubold et al., 2011) bind cytochrome c and undergo nucleotide exchange to promote assembly of a heptameric apoptosome. CARDs are flexibly tethered to NBDs in the central hub by CARD-α8 linkers (Yuan et al., 2010).
C. An extended Dark monomer was extracted from the apoptosome model and is shown on the left. In vitro assembly requires dATP to form single and double rings, as shown on the right.

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.
7.
Figure 5

Figure 5. Conformational transitions in Apaf-1 during apoptosome assembly. From: Apoptosome structure, assembly and procaspase activation.

A. (left) A homology model of an inactive human Apaf-1 monomer with bound ADP is shown without the N-terminal CARD. (right) Cytochrome c binding to β-propellers induces a conformational change that may promote nucleotide exchange and assembly. Apaf-1 monomers have been aligned on their WHD-HD2 modules. The direction of view is approximately along the 7-fold axis of the apoptosome for the molecule on the right.
B. The β7-propeller acts like a clamp to pin cytochrome c between the propellers.
C. A close-up is shown of the rotation of WHD relative to the NBD and HD1 pair that occurs upon nucleotide exchange. The associated HD2 arm and β-propellers are not shown. The HD1-WHD loop (marked with an asterisk) with an S/TxYxY motif flips to interact with the ribose region of the bound nucleotide during, while the WHD-HD2 arm rotates. Helices α8, α12 and α13 also move during apoptosome assembly.

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.
8.
Figure 3

Figure 3. Top views of worm, human and fly apoptosomes. From: Apoptosome structure, assembly and procaspase activation.

A. (top left) The central hub of the C. elegans apoptosome has quasi 8-fold symmetry. (lower right) CARDs from the A and B monomers of CED-4 form two tetrameric rings stacked along the 8-fold axis of the hub to create an apoptosome with overall 4-fold symmetry (Qi et al., 2010; 3LQQ).
B. The human apoptosome contains seven Apaf-1 molecules whose CARDs are disordered in the ground state (Yuan et al., 2010; submitted).
C. A Drosophila single ring apoptosome is shown with eight CARDs that bind to the lateral surface of their respective NBDs to form a crown (Yuan et al., 2011a; 1VT4, 3IZ8).
D. The CARD crown has been removed to show the similarity of the octagonal fly apoptosome and the heptameric Apaf-1 apoptosome in top views (compare with panel B). Note that mammalian cytochrome c does not bind to Dark in these complexes.

Shujun Yuan, et al. Structure. 2013 April 2;21(4):501-515.

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