ArticleThe Biochemical journal2015
An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein.
Article in The Biochemical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy.JCI insight · 2025Article
- Conformational transition of the Ixodes ricinus salivary serpin Iripin-4.Acta crystallographica. Section D, Structural biology · 2023Article
- The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant.International journal of molecular sciences · 2021Article
- Scaling Concepts in Serpin Polymer Physics.Materials (Basel, Switzerland) · 2021Article
- The molecular species responsible for αThe FEBS journal · 2021Article
- Development of a small molecule that corrects misfolding and increases secretion of Z αEMBO molecular medicine · 2021Article
- New Therapeutic Targets for Alpha-1 Antitrypsin Deficiency.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2018Article
- Article
- An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour.The Biochemical journal · 2016Article
- Cellular folding pathway of a metastable serpin.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Deficiency Mutations of Alpha-1 Antitrypsin. Effects on Folding, Function, and Polymerization.American journal of respiratory cell and molecular biology · 2016Article
- Production and application of polyclonal and monoclonal antibodies against Spiroplasma eriocheiris.Scientific reports · 2015Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
A monoclonal antibody (mAb) that binds to a transient intermediate may act as a catalyst for the corresponding reaction; here we show this principle can extend on a macro molecular scale to the induction of mutant-like oligomerization in a wild-type protein. Using the common pathogenic E342K (Z) variant of α1-antitrypsin as antigen-whose native state is susceptible to the formation of a proto-oligomeric intermediate-we have produced a mAb (5E3) that increases the rate of oligomerization of the wild-type (M) variant. Employing ELISA, gel shift, thermal stability and FRET time-course experiments, we show that mAb5E3 does not bind to the native state of α1-antitrypsin, but recognizes a cryptic epitope in the vicinity of the post-helix A loop and strand 4C that is revealed upon transition to the polymerization intermediate, and which persists in the ensuing oligomer. This epitope is not shared by loop-inserted monomeric conformations. We show the increased amenity to polymerization by either the pathogenic E342K mutation or the binding of mAb5E3 occurs without affecting the energetic barrier to polymerization. As mAb5E3 also does not alter the relative stability of the monomer to intermediate, it acts in a manner similar to the E342K mutant, by facilitating the conformational interchange between these two states.
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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.