Structural basis for executioner caspase recognition of P5 position in substrates

Posted On May 14, 2014
Categories Diabetes

Caspase-3, -6 and -7 cleave many proteins at
specific sites to induce apoptosis. Their recognition of the
P5 position in substrates has been investigated by kinetics,
modeling and crystallography. Caspase-3 and -6 recognize
P5 in pentapeptides as shown by enzyme activity data and
interactions observed in the crystal structure of caspase-3/
LDESD and in a model for caspase-6. In caspase-3 the P5
main-chain was anchored by interactions with Ser209 in
loop-3 and the P5 Leu side-chain interacted with Phe250
and Phe252 in loop-4 consistent with 50% increased
hydrolysis of LDEVD relative to DEVD. Caspase-6 formed
similar interactions and showed a preference for polar P5 in
QDEVD likely due to interactions with polar Lys265 and
hydrophobic Phe263 in loop-4. Caspase-7 exhibited no
preference for P5 residue in agreement with the absence of
P5 interactions in the caspase-7/LDESD crystal structure.
Initiator caspase-8, with Pro in the P5-anchoring position
and no loop-4, had only 20% activity on tested pentapeptides
relative to DEVD. Therefore, caspases-3 and -6 bind
P5 using critical loop-3 anchoring Ser/Thr and loop-4 sidechain
interactions, while caspase-7 and -8 lack P5-binding
residues.

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