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Cited by 753Protein Structure and DynamicsChemical Synthesis and AnalysisProtein purification and stability

Natural β-sheet proteins use negative design to avoid edge-to-edge aggregation

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Richardson, Jane S., Richardson, David C.·2002·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.052706099PMC PMC122420
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Abstract

The fact that natural β-sheet proteins are usually soluble but that fragments or designs of β structure usually aggregate suggests that natural β proteins must somehow be designed to avoid this problem. Regular β-sheet edges are dangerous, because they are already in the right conformation to interact with any other β strand they encounter. We surveyed edge strands in a large sample of all-β proteins to tabulate features that could protect against further β-sheet interactions. β-barrels, of course, avoid edges altogether by continuous H-bonding around the barrel cylinder. Parallel β-helix proteins protect their β-sheet ends by covering them with loops of other structure. β-propeller and single-sheet proteins use a combination of β-bulges, prolines, strategically placed charges, very short edge strands, and loop coverage. β-sandwich proteins favor placing an inward-pointing charged side chain on one of the edge strands where it would be buried by dimerization; they also use bulges, prolines, and other mechanisms. One recent β-hairpin design has a constrained twist too great for accommodation into a larger β-sheet, whereas some β-sheet edges are protected by the bend and reverse twist produced by an Lβ glycine. All free edge strands were seen to be protected, usually by several redundant mechanisms. In contrast, edge strands that natively form β H-bonded dimers or rings have long, regular stretches without such protection. These results are relevant to understanding how proteins may assemble into β-sheet amyloid fibers, and they are especially applicable to the de novo design of β structure. Many edge-protection strategies used by natural proteins are beyond our current abilities to constrain by design, but one possibility stands out as especially useful: a single charged side chain near the middle of what would ordinarily be the hydrophobic side of the edge β strand. This minimal negative-design strategy changes only one residue, requires no backbone distortion, and is easy to design. The accompanying paper [Wang, W. & Hecht, M. H. (2002) Proc. Natl. Acad. Sci. USA 99, 2760–2765] makes use of the inward-pointing charge strategy with great success, turning highly aggregated β-sandwich designs into soluble monomers.

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  • Inward-pointing charged side chains in edge strands are a known negative design principle that prevents aggregation of soluble β-sandwich proteins.

    “Related to these findings, inward-pointing charged side chains in edge strands are known to be a common negative design principle that prevents aggregation of soluble β-sandwich proteins (68) and has been employed to convert de novo amyloid fibrils into monomeric β-sheet proteins (69).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [68]

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Cited by

Sorted by citations

Authors
Richardson, J. S., & Richardson, D. C.
Affiliations
Duke University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2002-03-05
Volume
99
Issue
5
Pages
2754-2759
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.052706099
PMC
PMC122420
OpenAlex
W2145487893
Cited by
753
References
1
Citations by year
2026: 14 · 2025: 13 · 2024: 20 · 2023: 20 · 2022: 27 · 2021: 24 · 2020: 21 · 2019: 33 · 2018: 26 · 2017: 24 · 2016: 40 · 2015: 24 · 2014: 36 · 2013: 28 · 2012: 41
FWCI
15.22
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM015000, GM15000)
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 › Protein purification and stability
Keywords
beta-sheet proteins, negative design, all-beta proteins, beta-barrel, beta-helix, beta-propeller, beta-sandwich, beta-hairpin, beta-bulge, proline, charged side chains, protein solubility, de novo protein design
MeSH terms
Amino Acid Sequence, Models, Molecular, Molecular Sequence Data, Proteins, Protein Structure, Secondary, Protein Folding

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