Caspase-1 recognizes extended cleavage sites in its natural substrates.
OBJECTIVE
The preferred amino acids in the proteolytic sites have been considered to be similar between caspase-1 and caspase-9, which do not support their differential functions in inflammatory pyroptosis and apoptosis. We attempted to solve this problem.


METHODS
We analyzed the flanking 20 amino acid residues in the cleavage sites in 34 caspase-1 and 11 capase-9 experimentally identified substrates.


RESULTS
This study has made the following findings: first, we verified that caspase-1 and caspase-9 shared 100% aspartic acid in the P1 position. However, the structures in the cleavage sites of most caspase-1 substrates are different from that of caspase-9 substrates in the following three aspects, (a) the amino acid residues with the statistically high frequencies; (b) the hydrophobic amino acid occurrence frequencies; and (c) the charged amino acid occurrence frequencies; second, the amino acid pairs P1-P1' are different; third, our identified cleavage site patterns are useful in the prediction for the 91.4% cleavage sites of 35 new caspase-1 substrates.


CONCLUSIONS
Since most caspase-1 substrates are involved in vascular function, inflammation and atherogenesis, our novel structural patterns for the caspases' substrates are significant in developing new diagnostics and therapeutics.
Shen
Jerry
J
Department of Pharmacology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, United States.
Yin
Ying
Y
Mai
Jietang
J
Xiong
Xinyu
X
Pansuria
Meghana
M
Liu
Jingshan
J
Maley
Erin
E
Saqib
Najam Us
NU
Wang
Hong
H
Yang
Xiao-Feng
XF
D000596:Amino Acids / Q000737:chemistry; D017209:Apoptosis; D001665:Binding Sites; D020170:Caspase 1 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation; D008954:Models, Biological; D011485:Protein Binding; D013379:Substrate Specificity
D000596:Amino Acids; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1