ArticleThe Journal of biological chemistry2019
Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 31 citations in OpenAlex.
- Integrated genome-wide high-throughput screening and functional validation identifies Sm proteins as essential splicing regulators for gastric cancer progression.Functional & integrative genomics · 2026Article
- Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease.Cell discovery · 2025Review
- An NMR sample preparation case study: Considerations for the self-destructive protease caspase-6.PloS one · 2025Article
- Evolution of Caspases and the Invention of Pyroptosis.International journal of molecular sciences · 2024Review
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Evolution of the folding landscape of effector caspases.The Journal of biological chemistry · 2021Article
- Exogenous Introduction of Initiator and Executioner Caspases Results in Different Apoptotic Outcomes.JACS Au · 2021Article
- Great balls of fire: activation and signalling of inflammatory caspases.Biochemical Society transactions · 2021Review
- Rare CASP6N73T variant associated with hippocampal volume exhibits decreased proteolytic activity, synaptic transmission defect, and neurodegeneration.Scientific reports · 2021Article
- Tracking exogenous intracellular casp-3 using split GFP.Protein science : a publication of the Protein Society · 2021Article
- Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics.Computational and structural biotechnology journal · 2021Article
- Caspases from scleractinian coral show unique regulatory features.The Journal of biological chemistry · 2020Article
- Extended subsite profiling of the pyroptosis effector protein gasdermin D reveals a region recognized by inflammatory caspase-11.The Journal of biological chemistry · 2020Article
- Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity.The Biochemical journal · 2019Review
- Caspase-7 uses RNA to enhance proteolysis of poly(ADP-ribose) polymerase 1 and other RNA-binding proteins.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Caspases are cysteine-aspartic proteases involved in the regulation of programmed cell death (apoptosis) and a number of other biological processes. Despite overall similarities in structure and active-site composition, caspases show striking selectivity for particular protein substrates. Exosites are emerging as one of the mechanisms by which caspases can recruit, engage, and orient these substrates for proper hydrolysis. Following computational analyses and database searches for candidate exosites, we utilized site-directed mutagenesis to identify a new exosite in caspase-6 at the hinge between the disordered N-terminal domain (NTD), residues 23-45, and core of the caspase-6 structure. We observed that substitutions of the tri-arginine patch Arg-42-Arg-44 or the R44K cancer-associated mutation in caspase-6 markedly alter its rates of protein substrate hydrolysis. Notably, turnover of protein substrates but not of short peptide substrates was affected by these exosite alterations, underscoring the importance of this region for protein substrate recruitment. Hydrogen-deuterium exchange MS-mediated interrogation of the intrinsic dynamics of these enzymes suggested the presence of a substrate-binding platform encompassed by the NTD and the 240's region (containing residues 236-246), which serves as a general exosite for caspase-6-specific substrate recruitment. In summary, we have identified an exosite on caspase-6 that is critical for protein substrate recognition and turnover and therefore highly relevant for diseases such as cancer in which caspase-6-mediated apoptosis is often disrupted, and in neurodegeneration in which caspase-6 plays a central role.
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