A De Novo Designed Coiled-Coil Peptide with a Reversible pH-Induced Oligomerization Switch
Open accessAbstract
Protein conformational switches have many useful applications but are difficult to design rationally. Here we demonstrate how the isoenergetic energy landscape of higher-order coiled coils can enable the formation of an oligomerization switch by insertion of a single destabilizing element into an otherwise stable computationally designed scaffold. We describe a de novo designed peptide that was discovered to switch between a parallel symmetric pentamer at pH 8 and a trimer of antiparallel dimers at pH 6. The transition between pentamer and hexamer is caused by changes in the protonation states of glutamatic acid residues with highly upshifted pKa values in both oligomer forms. The drastic conformational change coupled with the narrow pH range makes the peptide sequence an attractive candidate for introduction of pH sensing into other proteins. The results highlight the remarkable ability of simple-α helices to self-assemble into a vast range of structural states.
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Achieving the desired balance between multiple target coiled-coil states often requires several rounds of trial-and-error and a detailed understanding of the energetic factors that discriminate between alternative topologies and oligomerization states.
“While this has been accomplished in a number of cases,18−31 achieving the desired balance between multiple target coiled-coil states often requires several rounds of trial-and-error and a detailed understanding of the energetic factors that discriminate between alternative topologies and oligomerization states.”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [25]
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“Remaining challenges in coiled-coil design include making coiled coil-based switches ( 31-36 ), and using our understanding to intervene in biological processes directly in situ .”
BackgroundEngineering and characterization of a pH‐sensitive homodimeric antiparallel coiled coil
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De novo design of proteins with two isoenergetic but structurally divergent ground states
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“The antennafinger/ZiCo/Sw2(Ambroggio and Kuhlman, 2006; Cerasoli et al., 2005; Hori and Sugiura, 2004) and pHios(Lizatović et al., 2016) switches represent the largest structural changes with two defined states to date, but both involve changes in oligomerization state.”
Background
- Authors
- Lizatović, R., Aurelius, O., Stenström, O., Drakenberg, T., Akke, M., Logan, D. T., & André, I.
- Affiliations
- Lund University (SE)
- Corresponding author
- André, Ingemar
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 24
- Issue
- 6
- Pages
- 946-955
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2347038344
- Cited by
- 48
- References
- 0
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Swedish Research Council (2011-5681, 2014-5815)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- coiled-coil peptides, de novo peptide design, conformational switching, pKa shift, antiparallel dimer, pH sensing
- MeSH terms
- Circular Dichroism, Hydrogen-Ion Concentration, Models, Molecular, Peptides, Protein Conformation, Proteins, Protein Structure, Secondary
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