The rate-limiting steps for the folding of an antibody scFv fragment
Open accessAbstract
The refolding kinetics of a single‐chain Fv (scFv) fragment, derived from the phosphorylcholine binding antibody McPC603, was investigated. Both prolyl‐peptide bonds which are cis in the native state affect the refolding kinetics of long‐term denatured protein. The rate‐limiting step is the trans→cis isomerization at the ProL95‐peptide bond, which is catalyzed by peptidyl‐prolyl‐cis/trans‐isomerase (PPIase), and is the prerequisite for correct V H/V L domain association. Refolding of short‐term denatured protein resulted in complex refolding kinetics, too. This kinetic heterogeneity could be ascribed to cis→trans re‐isomerization at the ProL95‐peptide bond to the wrong conformation in a folding intermediate. PPIase was shown to increase the fraction of slowly folding species, thereby competing with the fast folding of short‐term denatured scFv, having native proline conformations. A trapped intermediate is rapidly populated, and the return from this state becomes rate‐limiting.
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The slow isomerization of the peptide bond preceding Pro-L95 is important because it must be in the cis conformation for formation of the native VH/VL interface.
“Pioneering studies reported by Plückthun and coworkers [164,165] on the aggregation properties of scFv fragments, demonstrated that the slow isomerization of the peptide bond preceding Pro-L95 is important because it must be in the cis conformation for the formation of the native VH/VL interface.”
From Evolution of Escherichia coli Expression System in Producing Antibody Recombinant Fragments (2020) · cites this paper as [165]
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- Segal, D.M., Padlan, E.A., Cohen, G.H., Rudikoff, S., Potter, M. and Davies, D.R. (1974) Proc. Natl. Acad. Sci. USA 71, 4298- 4302.
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Protein quality control in the ER: The recognition of misfolded proteins
Määttänen, P., Gehring, K., Bergeron, J. J. M., & Thomas, D. Y. (2010) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2010.03.006 · Cited by 284 · see citing works
Evolution of Escherichia coli Expression System in Producing Antibody Recombinant Fragments
Sandomenico, A., Sivaccumar, J. P., & Ruvo, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176324 · Cited by 134 · see citing works
- Authors
- Jäger, M., & Plückthun, A.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Plückthun, Andreas
- ORCID
- Plückthun, Andreas
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 1997-11-24
- Volume
- 418
- Issue
- 1-2
- Pages
- 106-110
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W1982664434
- Cited by
- 44
- References
- 0
- Citations by year
- 2024: 1 · 2020: 1 · 2019: 3 · 2017: 2 · 2014: 2 · 2013: 3
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- scFv, antibody fragments, protein refolding kinetics, rate-determining step, cis-trans isomerization, proline isomerization, peptidyl-prolyl isomerase, folding intermediates, kinetic heterogeneity
- MeSH terms
- Amino Acid Sequence, Immunoglobulin Fragments, Immunoglobulin Variable Region, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Kinetics, Models, Molecular, Proline, Protein Conformation, Protein Denaturation, Recombinant Proteins, Mutagenesis, Site-Directed, Point Mutation, Protein Structure, Secondary, Protein Folding, Peptidylprolyl Isomerase
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