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Review
. 2012 Apr 16:1:e201204007.
doi: 10.5936/csbj.201204007. eCollection 2012.

Structural biology of the intrinsic cell death pathway: what do we know and what is missing?

Erinna F Lee  1 , W Douglas Fairlie  1
Affiliations
Review

Structural biology of the intrinsic cell death pathway: what do we know and what is missing?

Erinna F Lee et al. Comput Struct Biotechnol J. .
No abstract available

Keywords: Apaf-1; Apoptosis; Apoptosome; BH3 domain; Bax; Bcl-2.

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Figures

Figure 1
Figure 1
A) Schematic of the Bcl-2 regulated cell death in humans. B) Domain architecture of the Bcl-2 family of proteins. These proteins are characterized by the presence of up to 4 regions of sequence homology, known as Bcl-2 homology (BH) domains. C) The structure of the pro-survival protein, Bcl-xL (PDB: 1MAZ) comprises a helical bundle arrangement that typifies the Bcl-2 protein family fold. Surface electrostatic representation of D) Bcl-xL and E) Bfl-1 bound to Bim BH3 peptide show different charge distributions in the BH3 domain binding groove (PDB: 3FDL and 2VM6 respectively). F) Structure of the multi-domain pro-apoptotic protein, Bax (PDB: 1F16). The structure resembles that of the pro-survival protein and has the C-terminal α9 helix binding in the canonical hydrophobic groove. G) The only BH3-only protein, Bid, has a three-dimensional structure (PDB: 2BID) similar to that of the pro-survival and multi-domain pro-apoptotic proteins. Only Bid and possibly Bik are structured BH3-only proteins, the remaining members of this sub-class are thought to be intrinsically unstructured proteins. H) The structure of the BH3 domain from Bim (pink) bound to Bcl-xL (green) (PDB: 3FDL) is typical of interactions between BH3 domains from pro-apoptotic proteins and pro-survival proteins. I) Overlay of structures of Bcl-xL from complexes of it in its apo form (yellow, PDB: 1PQ0), or bound to ABT-737 (green, PDB: 2XYJ), an ABT-737 analogue (blue, PDB: 3INQ) or Bim BH3 peptide (pink, PDB: 3FDL) highlights significant differences in the arrangement of helices α3 and α4 that line the ligand binding groove. J) CED-9 also undergoes significant conformational changes upon binding the BH3 domain from Egl-1. The unstructured loop connecting helices α4-α5 (boxed) moves significantly in the complexed structure (pink, peptide has been removed for clarity, PDB: 1TY4), compared to in apo-CED-9 (blue, PDB: 1OHU).
Figure 2
Figure 2
A) Crystal structure of Apaf-1 (PDB: 3SFZ). The domains are colored as follows: NBD (pink), HD1 (blue), WHD (yellow), HD2 (green), WD1 (seven blade propellor, orange), WD2 (eight blade propellor, teal). B) Cryo-EM structure of the DARK apoptosome (PDB: 3IZ8) shows an octameric platform (color coding as in part A); C) Schematic of the apoptotic cell death pathway in C.elegans. D) Crystal structure (PDB: 2A5Y) of CED-9 (green) bound to a CED-4 dimer (subunits in blue and pink, E) Top and F) side views of the crystal structure of the octameric CED-4 apoptosome (PDB: 3LQQ; CARD: grey, α/β-fold: pink, HD1: blue, WHD: yellow, HD2: green).
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