Unfolding Death Proteins

Science's STKE  06 Mar 2001:
Vol. 2001, Issue 72, pp. tw7
DOI: 10.1126/stke.2001.72.tw7

One pathway involved in controlling apoptosis that has been characterized in Drosophila, but not other systems, is the pro-apoptotic pathway involving Reaper and the Reaper inhibitor Scythe. Scythe has a BAG domain, which is also present in the bcl-2 interacting protein BAG-1. The BAG domain mediates the interaction of BAG-1 with the heat shock protein, hsp70, and uncouples ATP hydrolysis from release of substrate by the chaperone. Investigations with Scythe in vitro and in vivo confirm that Scythe can also interact with hsp70 through the BAG domain and can inhibit chaperone-mediated protein refolding. Reaper disrupted the interaction between Scythe and hsp70. Surprisingly, the Scythe BAG domain was necessary and sufficient for inhibition of Reaper-stimulated apoptosis. The authors propose that the antiapoptotic activity of Scythe is to sequester cytochrome c-releasing proteins and that Reaper promotes the dissociation of Scythe from the hsp70 complex, thus allowing the cytochrome c-releasing proteins to fold and promote apoptosis.

K. Thress, J. Song, R. I. Morimoto, S. Kornbluth, Reversible inhibition of Hsp70 chaperone function by Scythe and Reaper. EMBO J. 20, 1033-1041 (2001). [Abstract] [Full Text]