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Related Concept Videos

Protein Folding01:25

Protein Folding

8.0K
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...
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Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
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Protein Denaturation01:28

Protein Denaturation

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The function of proteins depends on their native three-dimensional structure, which is dictated by the amino acid sequence of the specific protein. Folding of the polypeptide chain takes place under specific conditions that energetically favor the folded conformation. In contrast, protein denaturation occurs spontaneously under unfavorable conditions that disrupt the integrity of the folded conformation. Thus, the chemical and physical environment of a protein, such as significant changes in pH...
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The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Improving Translational Accuracy02:07

Improving Translational Accuracy

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Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
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Amyloid Fibrils03:03

Amyloid Fibrils

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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining,...
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Microfluidic Mixers for Studying Protein Folding
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Microfluidic Mixers for Studying Protein Folding

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Targeting the protein folding transition state by mutation: Large scale (un)folding rate accelerations without

Luis A Campos1,2, Victor Muñoz3,4

  • 1Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Madrid, Spain.

Protein Science : a Publication of the Protein Society
|June 12, 2024
PubMed
Summary

Protein folding rates can be engineered by targeting the folding transition state (FTS). A new strategy selectively stabilized CI2

Keywords:
folding ratesfolding transition statemutational analysisnatural selectionprotein engineeringprotein stabilityunfolding rates

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Area of Science:

  • Protein dynamics and biophysics
  • Protein engineering and design

Background:

  • Protein folding and unfolding rates are crucial for biological function and homeostasis.
  • Optimizing these rates without altering native stability is a key challenge in protein engineering.
  • Mutations typically affect folding and unfolding rates inversely, complicating design efforts.

Purpose of the Study:

  • To engineer protein folding and unfolding rates by targeting the folding transition state (FTS).
  • To investigate the role of the FTS in the stability and function of chymotrypsin inhibitor 2 (CI2).

Main Methods:

  • Targeted mutation of the CI2 folding transition state (FTS).
  • Analysis of folding and unfolding rates using kinetic experiments.
  • Assessment of protein stability and proteolytic degradation sensitivity.

Main Results:

  • A four-mutation CI2 variant selectively stabilized the FTS.
  • This variant exhibited >250-fold faster folding and unfolding rates with unchanged native stability.
  • The engineered CI2 lost its inhibitory activity and became more susceptible to degradation.

Conclusions:

  • Protein (un)folding rates can be precisely modulated by targeting specific residues and interactions within the FTS.
  • Evolution has optimized the CI2 FTS for kinetic stability, enabling its function as a protease inhibitor.
  • This FTS-centric design approach offers a promising strategy for predicting and engineering protein dynamics.