ArticleProceedings of the National Academy of Sciences of the United States of America2013
Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 43 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
43 citing papers in PubMed, 64 citations in OpenAlex.
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- Non-specificity as the sticky problem in therapeutic antibody development.Nature reviews. Chemistry · 2022Review
- Simultaneous Maturation of Single Chain Antibody Stability and Affinity by CHO Cell Display.Bioengineering (Basel, Switzerland) · 2022Article
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- Driving CARs with alternative navigation tools - the potential of engineered binding scaffolds.The FEBS journal · 2021Review
- Structural Basis of Antibody Conformation and Stability Modulation by Framework Somatic Hypermutation.Frontiers in immunology · 2021Article
- Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility.Biochemical engineering journal · 2018Article
- Reduction of Nonspecificity Motifs in Synthetic Antibody Libraries.Journal of molecular biology · 2018Article
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- Insights into the Structural Basis of Antibody Affinity Maturation from Next-Generation Sequencing.Frontiers in immunology · 2018Review
- Principles for computational design of binding antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Arginine mutations in antibody complementarity-determining regions display context-dependent affinity/specificity trade-offs.The Journal of biological chemistry · 2017Article
- The role of Antibody Vκ Framework 3 region towards Antigen binding: Effects on recombinant production and Protein L binding.Scientific reports · 2017Article
- Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells.International immunology · 2017Article
- Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability.Scientific reports · 2017Article
- Biophysical properties of the clinical-stage antibody landscape.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
Corrections and comments
- Retraction · 2017-08-30Civil Proceedings · Concerns/Issues about Data · Concerns/Issues about Results and/or Conclusions · Investigation by Company/Institution · Investigation by Journal/Publisher ·
- Commented on by
- Retracted
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Somatic hypermutation and clonal selection lead to B cells expressing high-affinity antibodies. Here we show that somatic mutations not only play a critical role in antigen binding, they also affect the thermodynamic stability of the antibody molecule. Somatic mutations directly involved in antigen recognition by antibody 93F3, which binds a relatively small hapten, reduce the melting temperature compared with its germ-line precursor by up to 9 °C. The destabilizing effects of these mutations are compensated by additional somatic mutations located on surface loops distal to the antigen binding site. Similarly, somatic mutations enhance both the affinity and thermodynamic stability of antibody OKT3, which binds the large protein antigen CD3. Analysis of the crystal structures of 93F3 and OKT3 indicates that these somatic mutations modulate antibody stability primarily through the interface of the heavy and light chain variable domains. The historical view of antibody maturation has been that somatic hypermutation and subsequent clonal selection increase antigen-antibody specificity and binding energy. Our results suggest that this process also optimizes protein stability, and that many peripheral mutations that were considered to be neutral are required to offset deleterious effects of mutations that increase affinity. Thus, the immunological evolution of antibodies recapitulates on a much shorter timescale the natural evolution of enzymes in which function and thermodynamic stability are simultaneously enhanced through mutation and selection.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.