ArticleProceedings of the National Academy of Sciences of the United States of America2013
Both the cis-trans equilibrium and isomerization dynamics of a single proline amide modulate β2-microglobulin amyloid assembly.
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. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 84 citations in OpenAlex.
- Distinct Molten-Globule Conformations in an Interacting Protein Domain Resolved byAngewandte Chemie (International ed. in English) · 2026Article
- Post-Translational Isoaspartate Promotes Amyloid Formation in βAngewandte Chemie (International ed. in English) · 2026Article
- Structural and dynamic similarities of nanofibrils and microparticles of engineered spider silk proteins probed by solid-state NMR spectroscopy.Protein science : a publication of the Protein Society · 2026Article
- Advances in the chemical synthesis of human proteoforms.Science China. Life sciences · 2025Review
- Single-molecule nanopore sensing of prolineChemical science · 2025Article
- Stabilization of a miniprotein fold by an unpuckered proline surrogate.Communications chemistry · 2025Article
- Site-Specific Incorporation of Fluorinated Prolines into Proteins and Their Impact on Neighbouring Residues.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Incorporation of Aliphatic Proline Residues into Recombinantly Produced Insulin.ACS chemical biology · 2023Article
- Probing Peptidylprolyl Bond cis/trans Status Using DistalChemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Early-Stage Oligomerization of Prion-like Polypeptides Reveals the Molecular Mechanism of Amyloid-Disrupting Capacity by Proline Residues.The journal of physical chemistry. B · 2023Article
- Energetic Basis and Design of Enzyme Function Demonstrated Using GFP, an Excited-State Enzyme.Journal of the American Chemical Society · 2022Article
- Mutant libraries reveal negative design shielding proteins from supramolecular self-assembly and relocalization in cells.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Deciphering the Structure and Formation of Amyloids in Neurodegenerative Diseases With Chemical Biology Tools.Frontiers in chemistry · 2022Review
- Natural and Synthetic Halogenated Amino Acids-Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics.Molecules (Basel, Switzerland) · 2021Review
- Protein Design with Fluoroprolines: 4,4-Difluoroproline Does Not Eliminate the Rate-Limiting Step of Thioredoxin Folding.Chembiochem : a European journal of chemical biology · 2021Article
- Incorporation of proline analogs into recombinant proteins expressed in Escherichia coli.Methods in enzymology · 2021Article
- Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement.Beilstein journal of organic chemistry · 2021Review
- Dihedral Angle Measurements for Structure Determination by Biomolecular Solid-State NMR Spectroscopy.Frontiers in molecular biosciences · 2021Review
- Fluorine NMR study of proline-rich sequences using fluoroprolines.Magnetic resonance (Gottingen, Germany) · 2021Article
- A Proline-Based Tectons and Supramolecular Synthons for Drug Design 2.0: A Case Study of ACEI.Pharmaceuticals (Basel, Switzerland) · 2020Article
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2 authors at 1 institution in 1 country.
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Abstract
The human protein β2-microglobulin (β2m) aggregates as amyloid fibrils in patients undergoing long-term hemodialysis. Isomerization of Pro32 from its native cis to a nonnative trans conformation is thought to trigger β2m misfolding and subsequent amyloid assembly. To examine this hypothesis, we systematically varied the free-energy profile of proline cis-trans isomerization by replacing Pro32 with a series of 4-fluoroprolines via total chemical synthesis. We show that β2m's stability, (un)folding, and aggregation properties are all influenced by the rate and equilibrium of Pro32 cis-trans isomerization. As anticipated, the β2m monomer was either stabilized or destabilized by respective incorporation of (2S,4S)-fluoroproline, which favors the native cis amide bond, or the stereoisomeric (2S,4R)-fluoroproline, which disfavors this conformation. However, substitution of Pro32 with 4,4-difluoroproline, which has nearly the same cis-trans preference as proline but an enhanced isomerization rate, caused pronounced destabilization of the protein and increased oligomerization at neutral pH. More remarkably, these subtle alterations in chemical composition--incorporation of one or two fluorine atoms into a single proline residue in the 99 amino acid long protein--modulated the aggregation properties of β2m, inducing the formation of polymorphically distinct amyloid fibrils. These results highlight the importance of conformational dynamics for molecular assembly of an amyloid cross-β structure and provide insights into mechanistic aspects of Pro32 cis-trans isomerism in β2m aggregation.
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