7JL7

Zebrafish Caspase N213T

Summary for 7JL7

• Entry DOI: 10.2210/pdb7jl7/pdb
• Descriptor: Caspase 3, apoptosis-related cysteine protease a, ASP-GLU-VAL-ASP peptide, ... (4 entities in total)
• Functional Keywords: enzyme specificity; apoptosis; caspase; zebrafish; protein evolution, cell cycle
• Biological source: Danio rerio (Zebrafish); More
• Total number of polymer chains: 5
• Total formula weight: 63570.06

Authors

Clark, A.C.,Swartz, P.D. (deposition date: 2020-07-29, release date: 2021-01-27, Last modification date: 2023-10-18)

Primary citation

Yao, L.,Swartz, P.,Hamilton, P.T.,Clark, A.C.
Remodeling hydrogen bond interactions results in relaxed specificity of Caspase-3.
Biosci.Rep., 41:-, 2021

PubMed Abstract: Caspase (or cysteinyl-aspartate specific proteases) 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 with 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 with those required to access new conformational space for swapping substrate specificity, such as between caspases-3 and -6.

PubMed: 33448281
DOI: 10.1042/BSR20203495

Experimental method

X-RAY DIFFRACTION (2.05 Å)