Related Experiment Video

Updated: Feb 23, 2026

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
05:56

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Published on: October 13, 2022

1.8K

Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions

Kevin B Dagbay1, Jeanne A Hardy2

  • 1Department of Chemistry, University of Massachusetts, Amherst, MA 01002.

Proceedings of the National Academy of Sciences of the United States of America
|September 3, 2017
PubMed

Insights

Caspase-6 dynamics were mapped using hydrogen/deuterium exchange mass spectrometry (H/DX-MS). Understanding these conformational changes offers therapeutic strategies for neurodegenerative diseases like Alzheimer's and Parkinson's.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Caspase-6 is a key enzyme in neurodegenerative diseases, including Alzheimer's, Huntington's, and Parkinson's.
  • Targeting caspase-6 offers a potential therapeutic strategy for neurodegeneration.
  • Understanding caspase-6 dynamics and conformation is crucial for developing effective treatments.

Purpose of the Study:

  • To map local conformational flexibility changes in procaspase-6 during its activation process.
  • To investigate the role of specific regions and cleavage events in caspase-6 function.
  • To provide molecular insights for designing therapeutics against neurodegenerative disorders.

Main Methods:

  • Hydrogen/deuterium exchange mass spectrometry (H/DX-MS) was employed to analyze procaspase-6.
  • Conformational flexibility was assessed at discrete states reflecting sequential cleavage events.
  • The study examined changes in solvent exposure and flexibility across different caspase-6 regions.

Main Results:

  • Intramolecular cleavage at Asp-193 increased solvent exposure in substrate-binding loops (L1, L3, L4) and other regions.
  • Linker removal enhanced flexibility in the 130s and L2 regions, enabling substrate binding.
  • The prodomain is intrinsically disordered, but its removal protected the 26-32 region, suggesting a regulatory role.

Conclusions:

  • Molecular details of caspase-6 dynamics in solution were elucidated.
  • These findings provide a framework for developing targeted therapies for neurodegenerative diseases.
  • The study highlights the importance of caspase-6 conformational flexibility in its activation and function.
Keywords:
apoptosisconformational dynamicscysteine proteasehydrogen exchange MSneurodegeneration

More Related Videos

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

9.5K
Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages08:41

Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages

Published on: April 6, 2022

3.2K

Related Concept Videos

Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
14.3K
Protein Folding01:25

Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
11.8K
Protein Folding01:22

Protein Folding

Overview
128.7K
The Proteasome Structure01:17

The Proteasome Structure

The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
1.9K
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
13.5K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
8.8K