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Related Concept Videos

Antibody Structure01:10

Antibody Structure

Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
Antibody Structure01:10

Antibody Structure

Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
Antibody Structure and Classes01:25

Antibody Structure and Classes

Antibodies, also known as immunoglobulins, are produced by B cells in response to foreign substances, such as bacteria and viruses. These proteins are critical for recognizing and neutralizing these substances, protecting the body from potential harm.
The basic structure of an antibody consists of four protein chains: two identical heavy chains and two identical light chains. These chains are held together by disulfide bonds and other non-covalent interactions, forming a Y-shaped structure.
Hybridoma Technology01:31

Hybridoma Technology

Hybridoma technology is used for the large-scale production of monoclonal antibodies. Monoclonal antibodies bind to only a single antigenic determinant or epitope. Such antibodies are used in research, diagnostics, and disease therapy. The hybridoma technology established in 1975 by Georges Köhler and Cesar Milstein was awarded the Nobel Prize in Medicine in 1984 for revolutionizing research and therapy.
Hybridoma Selection
Commonly used fusion techniques — electroporation, polyethylene glycol...
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
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...

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Protein Engineering by Yeast Surface Display
05:49

Protein Engineering by Yeast Surface Display

Published on: November 29, 2024

Thermodynamically stable aggregation-resistant antibody domains through directed evolution.

Kristoffer Famm1, Lars Hansen, Daniel Christ

  • 1Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.

Journal of Molecular Biology
|January 18, 2008
PubMed
Summary
This summary is machine-generated.

Researchers developed a Darwinian selection method to create antibody domains resistant to acid aggregation. This approach yielded domains with enhanced thermodynamic stability and aggregation-resistant unfolded states, crucial for protein stability.

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Area of Science:

  • Protein engineering
  • Biophysics
  • Immunology

Background:

  • Protein aggregation is linked to unfolded or partially unfolded states, often triggered by heat or low pH.
  • Previous work utilized Darwinian selection on phage-displayed antibody variable domains to achieve resistance to heat-induced aggregation.
  • Selected domains exhibited low free energies of folding, suggesting limited thermodynamic stability.

Purpose of the Study:

  • To extend Darwinian selection to isolate human antibody variable domains resistant to acid-induced aggregation.
  • To investigate the thermodynamic properties and identify determinants of acid-aggregation resistance.
  • To generate domains combining thermodynamic stability with aggregation-resistant unfolded states.

Main Methods:

  • Phage display of antibody variable domain repertoires.
  • Selection for resistance to aggregation under acidic conditions (low pH).
  • Thermodynamic stability measurements (Delta G(N-D)(o)) under neutral and acidic conditions.
  • Identification of key amino acid residues contributing to aggregation resistance.

Main Results:

  • Selected domains demonstrated higher thermodynamic stabilities compared to those selected for thermal aggregation resistance.
  • Selected domains showed increased resistance to aggregation at low pH.
  • A specific determinant, Arginine at position 28 (Arg28), was identified as crucial for enhancing aggregation resistance at low pH without reducing thermodynamic stability.

Conclusions:

  • Darwinian selection can yield antibody domains with combined thermodynamic stability and resistance to aggregation in their unfolded states.
  • The selection process influences folding equilibrium, favoring domains with improved stability and aggregation resistance.
  • The identified Arg28 residue is a key factor in achieving acid-aggregation resistance in antibody domains.