Rare by Natural Selection: Disulfide-Bonded Supramolecular Antimicrobial Peptides

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Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
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Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids

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Yizhaq Engelberg1, Peleg Ragonis-Bachar1, Meytal Landau1,2

  • 1Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.

Biomacromolecules
|January 21, 2022
PubMed

Insights

Human LL-3717-29 antimicrobial peptides form fibrils. Disulfide bonds in LL-3717-29 mutants control fibril assembly and antibacterial activity, explaining natural selection against certain cysteine-containing peptides.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Microbiology

Background:

  • Human LL-3717-29 is a key antimicrobial peptide known for forming thermostable supramolecular fibrils.
  • These fibrils are implicated in surrounding and potentially inhibiting bacterial cells.

Purpose of the Study:

  • To elucidate the structural basis of LL-3717-29 fibril formation and its relation to antibacterial activity.
  • To investigate the role of specific cysteine substitutions and disulfide bonds in modulating fibril assembly and antimicrobial function.

Main Methods:

  • Crystal structure determination of LL-3717-29 with an I24C substitution.
  • Analysis of disulfide-bonded dimers and their assembly into helical fibrillar structures.
  • Assessment of position-dependent antibacterial activity of various cysteine mutants.

Main Results:

  • The crystal structure revealed disulfide-bonded dimers of LL-3717-29 I24C, which further assemble into densely packed helical fibrils.
  • Antibacterial activity was controllable and position-dependent in cysteine mutants, linked to disulfide bond regulation and supramolecular assembly.
  • Fibril morphology and antibacterial mechanisms may vary based on interactions with specific bacterial species.

Conclusions:

  • Intermolecular disulfide bonds critically influence the assembly of LL-3717-29 into functional supramolecular structures.
  • The sensitivity of these disulfide bonds to redox conditions may explain the natural selection against short helical antimicrobial peptides with odd cysteine numbers.

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