Scientific announcements are a bit like catching a bus — a long wait, and then two arrive at once. This was the case back in July, when the groups of Xiaodong Wang in Dallas and David Vaux in Melbourne independently described a new mammalian protein that promotes apoptosis. Its activity has now been further characterized, as Wang and colleagues report in Nature.

The protein in question — named Smac by Wang's group and DIABLO by Vaux and colleagues — promotes apoptosis by binding to and antagonizing members of the IAP (inhibitor of apoptosis protein) family. These IAPs have an anti-apoptotic activity because they bind and inhibit caspases, the key effectors of cell death.

In Drosophila, the activity of IAPs is countered by the imaginatively named Reaper, Hid and Grim proteins — hence the search for mammalian functional homologues. And, as described in the two initial reports, Smac/DIABLO fits the bill. It promotes apoptosis by binding to the IAPs, and prevents them from sequestering caspases.

But how does it do this? Wang and colleagues now provide clues with the crystal structure of Smac/DIABLO at a resolution of 2.2 Å. The structure reveals that Smac/DIABLO forms a homodimer in solution, so the authors first asked whether this is the functional form. They engineered missense mutations to perturb dimer formation, and found that the interaction of monomers with an IAP ( XIAP) was indeed disrupted (although not abolished).

At least one function of Smac/DIABLO is to stimulate the cleavage of procaspase 3 from an inactive procaspase precursor to the mature form, Caspase 3. Wang and co-workers reconstituted this function in vitro using purified recombinant components (including XIAP), then asked whether Smac/DIABLO might also promote the catalytic activity of mature caspase 3. They found that it could, and conclude that Smac/DIABLO triggers apoptosis through at least two mechanisms — it induces the proteolytic activation of procaspase 3, and also promotes the enzymatic activity of mature caspase 3.

Finally Wang and colleagues looked for other functional parallels with the Drosophila homologues. It turns out that, in both cases, the amino-terminal region is essential for function. The authors narrowed this down to just seven amino acids, which, on their own, are enough to activate procaspase 3 (albeit much less efficiently than the full-length protein). Given that the only region of sequence conservation in Grim, Reaper and Hid is the amino-terminal 14 amino acids, this work, say the authors, defines “an evolutionarily conserved structural and biochemical basis for the activation of apoptosis by Smac/DIABLO”.