TY - JOUR
T1 - Structure and activation mechanism of the Drosophila initiator caspase Dronc
AU - Yan, Nieng
AU - Huh, Jun R.
AU - Schirf, Virgil
AU - Demeler, Borries
AU - Hay, Bruce A.
AU - Shi, Yigong
PY - 2006/3/31
Y1 - 2006/3/31
N2 - Activation of an initiator caspase is essential to the execution of apoptosis. The molecular mechanisms by which initiator caspases are activated remain poorly understood. Here we demonstrate that the autocatalytic cleavage of Dronc, an important initiator caspase in Drosophila, results in a drastic enhancement of its catalytic activity in vitro. The autocleaved Dron forms a homodimer, whereas the uncleaved Dronc zymogen exists exclusively as a monomer. Thus the autocatalytic cleavage in Dronc induces its stable dimerization, which presumably allows the two adjacent monomers to mutually stabilize their active sites, leading to activation. Crystal structure of a prodomain-deleted Dronc zymogen, determined at 2.5 Å resolution, reveals an unproductive conformation at the active site, which is consistent with the observation that the zymogen remains catalytically inactive. This study revealed insights into mechanism of Dron activation, and in conjunction with other observations, suggests diverse mechanisms for the activation of initiator caspases.
AB - Activation of an initiator caspase is essential to the execution of apoptosis. The molecular mechanisms by which initiator caspases are activated remain poorly understood. Here we demonstrate that the autocatalytic cleavage of Dronc, an important initiator caspase in Drosophila, results in a drastic enhancement of its catalytic activity in vitro. The autocleaved Dron forms a homodimer, whereas the uncleaved Dronc zymogen exists exclusively as a monomer. Thus the autocatalytic cleavage in Dronc induces its stable dimerization, which presumably allows the two adjacent monomers to mutually stabilize their active sites, leading to activation. Crystal structure of a prodomain-deleted Dronc zymogen, determined at 2.5 Å resolution, reveals an unproductive conformation at the active site, which is consistent with the observation that the zymogen remains catalytically inactive. This study revealed insights into mechanism of Dron activation, and in conjunction with other observations, suggests diverse mechanisms for the activation of initiator caspases.
UR - http://www.scopus.com/inward/record.url?scp=33646839270&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646839270&partnerID=8YFLogxK
U2 - 10.1074/jbc.M513232200
DO - 10.1074/jbc.M513232200
M3 - Article
C2 - 16446367
AN - SCOPUS:33646839270
SN - 0021-9258
VL - 281
SP - 8667
EP - 8674
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 13
ER -