The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3.

Shujun Yuan, Xinchao Yu, John M Asara, John E Heuser, Steven J Ludtke, Christopher W Akey

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118-2526, USA.

Structure (London, England : 1993) 2011 Aug 10

filter terms:

Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway. We now provide further evidence that caspase recruitment domains of pc-9 and Apaf-1 form a CARD-CARD disk that is flexibly tethered to the apoptosome. In addition, a 3D reconstruction of the pc-9 apoptosome was calculated without symmetry restraints. In this structure, p20 and p10 catalytic domains of a single pc-9 interact with nucleotide binding domains of adjacent Apaf-1 subunits. Together, disk assembly and pc-9 binding create an asymmetric proteolysis machine. We also show that CARD-p20 and p20-p10 linkers play important roles in pc-9 activation. Based on the data, we propose a proximity-induced association model for pc-9 activation on the apoptosome. We also show that pc-9 and caspase-3 have overlapping binding sites on the central hub. These binding sites may play a role in pc-3 activation and could allow the formation of hybrid apoptosomes with pc-9 and caspase-3 proteolytic activities. Copyright © 2011 Elsevier Ltd. All rights reserved.

Citation

Shujun Yuan, Xinchao Yu, John M Asara, John E Heuser, Steven J Ludtke, Christopher W Akey. The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3. Structure (London, England : 1993). 2011 Aug 10;19(8):1084-96