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Structural basis for executioner caspase recognition of P5 position in substrates.

Fu G, Chumanevich AA, Agniswamy J, Fang B, Harrison RW, Weber IT
Apoptosis 13 1291-302 (2008)
Cited: 24 times
EuropePMC logo PMID: 18780184

Abstract

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 side-chain interactions, while caspase-7 and -8 lack P5-binding residues.

Articles - 3edr mentioned but not cited (1)

  1. Structural basis for executioner caspase recognition of P5 position in substrates. Fu G, Chumanevich AA, Agniswamy J, Fang B, Harrison RW, Weber IT. Apoptosis 13 1291-1302 (2008)


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  1. Caspase substrates and cellular remodeling. Crawford ED, Wells JA. Annu Rev Biochem 80 1055-1087 (2011)
  2. Small Molecule Active Site Directed Tools for Studying Human Caspases. Poreba M, Szalek A, Kasperkiewicz P, Rut W, Salvesen GS, Drag M. Chem Rev 115 12546-12629 (2015)

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  17. Letter MerCASBA: an updated and refined database of caspase substrates. Fridman A, Pak I, Butts BD, Hoek M, Nicholson DW, Mehmet H. Apoptosis 18 369-371 (2013)
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