Tadpole-like conformations of Huntingtin Exon 1 are characterized by conformational heterogeneity that persists regardless of polyglutamine length
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Abstract
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen-deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region. The surface area of the globular domain increases monotonically with polyQ length. This stimulates sharp increases in gain-of-function interactions in cells for expanded polyQ, and one of these interactions is with the stress-granule protein Fus. Our results highlight plausible connections between Httex1 structure and routes to neurotoxicity.
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Httex1 has a clear preference for forming tadpole-like conformations.
“A curious feature of the conformational ensembles was the discovery that Httex1 has a clear preference for forming tadpole-like conformations.94”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [94]
Conformational heterogeneity of the Httex1 ensemble derives from the diversity of compact conformations within the polyQ domain and the distribution of internal distances and orientations that characterize the Pro-rich region.
“Conformational heterogeneity of this ensemble derives from the diversity of compact conformations within the polyQ domain and the distribution of internal distances and orientations that characterize the Pro-rich region.”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [94]
These changes, as opposed to sharp conformational transitions as a function of polyQ length, are likely to influence the gain-of-function interactions that influence disease progression and neuronal death.
“These changes, as opposed to sharp conformational transitions as a function of polyQ length, are likely to influence the gain-of-function interactions that influence disease progression and neuronal death.”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [94]
The radius of gyration of the polyQ domain scales as n^1/3, where n is the number of Gln residues in the polyQ tract.
“The polyQ domain adopts globular conformations, wherein the radius of gyration scales as n 1/3 where n is the number of Gln residues in the polyQ tract.”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [94]
The polyQ domain of Httex1 adopts globular conformations.
“The polyQ domain adopts globular conformations, wherein the radius of gyration scales as n 1/3 where n is the number of Gln residues in the polyQ tract.”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [94]
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Self-citationRipaud, L., Chumakova, V., Antonin, M., Hastie, A. R., Pinkert, S., Körner, R., Ruff, K. M., Pappu, R. V., Hornburg, D., Mann, M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421313111 · Cited by 55 · see citing works
Self-citationThe complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1
Sethi, A., Bruell, S., Patil, N. A., et al. (2016) · Nature Communications · doi:10.1038/ncomms11344 · Cited by 55 · see citing works
Self-citationEmerging β-Sheet Rich Conformations in Supercompact Huntingtin Exon-1 Mutant Structures
Kang, H., Vázquez, F. X., Zhang, L., et al. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b00838 · Cited by 52 · see citing works
Secondary Structures of Native and Pathogenic Huntingtin N-Terminal Fragments
Długosz, M., & Trylska, J. (2011) · The Journal of Physical Chemistry B · doi:10.1021/jp206373g · Cited by 44 · see citing works
Darrow, M. C., Sergeeva, O. A., Isas, J. M., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.655373 · Cited by 43 · see citing works
Conformation Sensors that Distinguish Monomeric Proteins from Oligomers in Live Cells
Ramdzan, Y. M., Nisbet, R. M., Miller, J. M. L., Finkbeiner, S. M., Hill, A. F., & Hatters, D. M. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.03.011 · Cited by 40 · see citing works
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The Aggregation Free Energy Landscapes of Polyglutamine Repeats
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Radhakrishnan, A., Vitalis, A., Mao, A. H., Steffen, A. T., & Pappu, R. V. (2012) · The Journal of Physical Chemistry B · doi:10.1021/jp212637r · Cited by 36 · see citing works
Self-citationAnti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1
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Role of the Coiled-Coil Structural Motif in Polyglutamine Aggregation
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The Three-Dimensional Solution Structure of the SH2 Domain from p55blk Kinase
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Flagged first, then by citations
Research works printed but not linked: 3
- [49]Lyle N Das RK Pappu RV A quantitative measure for protein conformational heterogeneity J Chem Phys 2013 139 121907 24089719 PMC3724800
- [50]Vitalis A Wang X Pappu RV Atomistic simulations of the effects of polyglutamine chain length and solvent quality on conformational equilibria and spontaneous homodimerization J Mol Biol 2008 384 279 97 18824003 PMC2847503
- [67]Caron NS Desmond CR Xia J Truant R Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin Proc Natl Acad Sci U S A 2013 110 14610 5 23898200 PMC3767516
Cited by
Sorted by citations
AlphaFold and Implications for Intrinsically Disordered Proteins
Ruff, K. M., & Pappu, R. V. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167208 · Cited by 635 · see citing works
Self-citationUrbanek, A., Popovic, M., Morató, A., Estaña, A., Elena-Real, C. A., Mier, P., Fournet, A., Allemand, F., Delbecq, S., Andrade-Navarro, M. A., et al. (2020) · Structure · doi:10.1016/j.str.2020.04.008 · Cited by 66 · see citing works
Morató, A., Elena-Real, C. A., Popovic, M., Fournet, A., Zhang, K., Allemand, F., Sibille, N., Urbanek, A., & Bernadó, P. (2020) · Biomolecules · doi:10.3390/biom10101458 · Cited by 12 · see citing works
- Authors
- Newcombe, E. A., Ruff, K. M., Sethi, A., Ormsby, A. R., Ramdzan, Y. M., Fox, A., Purcell, A. W., Gooley, P. R., Pappu, R. V., & Hatters, D. M.
- Affiliations
- The University of Melbourne (AU)
- Washington University in St. Louis (US)
- The University of Western Australia (AU)
- Monash University (AU)
- Corresponding author
- Pappu, Rohit V.
- Hatters, Danny M.
- ORCID
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 430
- Issue
- 10
- Pages
- 1442-1458
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC5963539
- OpenAlex
- W2795651807
- Cited by
- 66
- References
- 104
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 13 · 2022: 10 · 2021: 13 · 2020: 13 · 2019: 8 · 2018: 3 · 2017: 1
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, other-oa)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by-nc-nd)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
- Funders
- Technion-Israel Institute of Technology (3200003)
- American Society for Biochemistry and Molecular Biology
- Institute of Infection and Immunity
- Monash University
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- huntingtin exon 1, polyglutamine expansion, Huntington's disease, conformational heterogeneity, neurotoxicity, hydrogen-deuterium exchange, hydrogen bonding, FUS protein
- MeSH terms
- Huntingtin Protein, Protein Domains, Gain of Function Mutation, Cell Line, Exons, Humans, Huntington Disease, Hydrogen Bonding, Peptides, RNA-Binding Proteins, Protein Structure, Secondary, RNA-Binding Protein FUS, Deuterium Exchange Measurement
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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