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Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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...
Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

Protein domains are small structurally independent units that are part of a single amino acid chain.  Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to form...
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...

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Proteasome allostery as a population shift between interchanging conformers.

Amy M Ruschak1, Lewis E Kay

  • 1Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA. amy.ruschak@case.edu

Proceedings of the National Academy of Sciences of the United States of America
|November 15, 2012
PubMed
Summary
This summary is machine-generated.

The 20S proteasome core particle (CP) exists in multiple conformations in solution. Activator binding or mutations shift these populations, altering proteolysis and offering therapeutic targets for proteasome inhibition.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • Protein degradation is vital for cellular homeostasis, cell cycle regulation, and immune peptide generation.
  • The 20S proteasome core particle (CP) is central to protein degradation, featuring a barrel-like structure of stacked rings.
  • Allosteric regulation of CP activity by activator complexes is known, but structural evidence remains limited.

Purpose of the Study:

  • To investigate the conformational dynamics of the 20S proteasome core particle (CP) in solution.
  • To elucidate the structural basis of allosteric regulation by activator complexes and small-molecule inhibitors.

Main Methods:

  • Methyl TROSY NMR spectroscopy was employed to study the 20S proteasome core particle (CP) in solution.
  • Conformational changes were monitored upon binding of the 11S activator, mutations, and inhibitor treatment.

Main Results:

  • The 20S proteasome core particle (CP) interconverts between multiple conformations in solution.
  • Binding of the 11S activator or mutations shifted the populations of these CP conformers.
  • These conformational shifts influence substrate proteolysis patterns and activator binding site structure.
  • Chloroquine binding also modulated CP conformer populations, indicating allosteric inhibition.

Conclusions:

  • The 20S proteasome core particle (CP) exhibits dynamic conformational heterogeneity in solution.
  • Allosteric regulation of the CP involves modulation of these conformational populations.
  • Understanding these dynamics provides insights into therapeutic strategies for proteasome-related diseases.