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Evolution of Caspase Allostery and Enzyme Specificity
Author(s) -
Clark Clay,
Grinshpon Robert,
Thomas Melvin E.,
Yao Liqi,
Shrestha Suman
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.528.10
Subject(s) - allosteric regulation , subfamily , caspase , biology , allosteric enzyme , enzyme , active site , phylogenetic tree , biochemistry , microbiology and biotechnology , gene , programmed cell death , apoptosis
We used phylogenetic, structural, and biophysical studies to examine the evolution of enzyme specificity and allosteric regulation in caspases. Caspase‐3 activation and function has been well defined during programmed cell death, but caspase activity, at low levels, is also required for cell development. We established a database, the CaspBase, for phylogenetic and ancestral reconstruction of caspases, which consists of >1,500 caspase genes. From this database, we resurrected ancestors of the caspase‐3, ‐6, ‐7 subfamily, and the common ancestor displays enzyme specificity similar to the initiator caspase subfamily from which it evolved. The specificities of the caspase‐3/‐7 and caspase‐6 enzymes evolved early, after the two lineages split. Structural studies of the ancestral enzymes identify changes in the active sites that result in changes in substrate selection. In contrast to enzyme activity, several allosteric sites evolved later in the lineages. We define interaction networks that facilitate the allosteric regulation in caspase‐3, and we show that, within a conserved loop, one site of phosphorylation evolved with the apoptotic caspases, while a second site is a more recent evolutionary event in mammalian caspase‐3. Localized changes in the loop propagate to the active site of the same protomer and disrupt substrate hydrolysis by facilitating transient ionic interactions with the catalytic histidine. In contrast, a cluster of hydrophobic amino acids in the dimer interface connects the conserved loop to the active site of the second protomer. The presence of the second modification in the conserved loop introduces a “kill switch” in mammalian caspase‐3. The data reveal how evolutionary changes in a conserved allosteric site result in both a common pathway for lowering activity during cell development as well as introducing a more recent cluster‐specific switch to abolish activity. Support or Funding Information UT Arlington This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .