PUBLICATION
Remodeling hydrogen bond interactions results in relaxed specificity of Caspase-3
- Authors
- Yao, L., Swartz, P., Hamilton, P.T., Clark, A.C.
- ID
- ZDB-PUB-210116-7
- Date
- 2021
- Source
- Bioscience Reports 41(1): (Journal)
- Registered Authors
- Keywords
- apoptosis, caspase, enzyme specificity, protein evolution, zebrafish
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Aspartic Acid/metabolism
- Caspase 3/chemistry
- Caspase 3/metabolism*
- Caspase 6/metabolism
- Humans
- Hydrogen Bonding
- Sequence Homology, Amino Acid
- Substrate Specificity
- Valine/metabolism
- Zebrafish
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism
- PubMed
- 33448281 Full text @ Biosci. Rep.
Citation
Yao, L., Swartz, P., Hamilton, P.T., Clark, A.C. (2021) Remodeling hydrogen bond interactions results in relaxed specificity of Caspase-3. Bioscience Reports. 41(1):.
Abstract
Caspase enzymes play important roles in apoptosis and inflammation, and the non-identical but overlapping specificity profiles (that is, cleavage recognition sequence) direct cells to different fates. Although all caspases prefer aspartate at the P1 position of the substrate, the caspase-6 subfamily shows preference for valine at the P4 position, while caspase-3 shows preference for aspartate. In comparison to human caspases, caspase-3a from zebrafish has relaxed specificity and demonstrates equal selection for either valine or aspartate at the P4 position. In the context of the caspase-3 conformational landscape, we show that changes in hydrogen bonding near the S3 subsite affect selection of the P4 amino acid. Swapping specificity with caspase-6 requires accessing new conformational space, where each landscape results in optimal binding of DxxD (caspase-3) or VxxD (caspase-6) substrate and simultaneously disfavors binding of the other substrate. Within the context of the caspase-3 conformational landscape, substitutions near the active site result in nearly equal activity against DxxD and VxxD by disrupting a hydrogen bonding network in the substrate binding pocket. The converse substitutions in zebrafish caspase-3a result in increased selection for P4 aspartate over valine. Overall, the data show that the shift in specificity that results in a dual function protease, as in zebrafish caspase-3a, requires fewer amino acid substitutions compared to those required to access new conformational space for swapping substrate specificity, such as between caspases-3 and -6.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping