Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction
Open accessAbstract
Significance: M proteins are major virulence factors of the widespread bacterial pathogen group A Streptococcus . The sequences of M proteins are antigenically variable, but have in common the tendency to form α-helical coiled coil structures. Paradoxically, these same sequences also contain a substantial number of amino acids that destabilize coiled coils. We present an explanation for this paradox in finding that destabilizing residues are essential for conformational dynamics in the M protein, and that these dynamics are required for interaction with human fibrinogen. Our work leads to the general conclusion that destabilizing residues are conserved through evolution in M proteins to enable functional interactions that are necessary for pathogenesis.
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Natural coiled coils are dynamic and play central roles in a multitude of biological functions.
“Natural coiled coils, on the other hand, are dynamic and play central roles in a multitude of biological functions.13−17”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [15]
Cites
Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus
Walker, M. J., Barnett, T. C., McArthur, J. D., Cole, J. N., Gillen, C. M., Henningham, A., Sriprakash, K. S., Sanderson-Smith, M. L., & Nizet, V. (2014) · Clinical Microbiology Reviews · doi:10.1128/cmr.00101-13 · Cited by 908 · see citing works
Self-citationThe HAMP Domain Structure Implies Helix Rotation in Transmembrane Signaling
Hulko, M., Berndt, F., Gruber, M., Linder, J. U., Truffault, V., Schultz, A., Martin, J., Schultz, J. E., Lupas, A. N., & Coles, M. (2006) · Cell · doi:10.1016/j.cell.2006.06.058 · Cited by 416 · see citing works
Helix sliding in the stalk coiled coil of dynein couples ATPase and microtubule binding
Kon, T., Imamula, K., Roberts, A. J., Ohkura, R., Knight, P. J., Gibbons, I. R., Burgess, S. A., & Sutoh, K. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1555 · Cited by 169 · see citing works
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Notari, E., Wood, C. W., & Michel, J. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.4c01695 · Cited by 4 · see citing works
- Authors
- Stewart, C. M., Buffalo, C. Z., Valderrama, J. A., Henningham, A., Cole, J. N., Nizet, V., & Ghosh, P.
- Affiliations
- University of California San Diego (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-08-10
- Volume
- 113
- Issue
- 34
- Pages
- 9515-9520
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5003295
- OpenAlex
- W2477195065
- Cited by
- 41
- References
- 3
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 8 · 2020: 1 · 2019: 8 · 2018: 5 · 2017: 4
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Office of Extramural Research, National Institutes of Health (T32 GM008326, R01 AI096387, R01 AI077780, T32 GM007240)
- American Heart Association (14PRE18320032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Streptococcal Infections and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- M1 protein, Streptococcus pyogenes, fibrinogen binding, protein conformational dynamics, intrinsically disordered proteins, thermal instability, protein-protein interaction, virulence factors, antigenic variation
- MeSH terms
- Protein Conformation, alpha-Helical, Amino Acid Sequence, Amino Acids, Antigens, Bacterial, Bacterial Outer Membrane Proteins, Binding Sites, Carrier Proteins, Cloning, Molecular, Escherichia coli, Fibrinogen, Genetic Vectors, Humans, Mutation, Protein Binding, Recombinant Proteins, Streptococcus pyogenes, Thermodynamics, Gene Expression, Protein Interaction Domains and Motifs
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