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Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
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Dipeptidyl peptidase IV processing activates Manduca sexta pro-moricin-6: structural basis of enhanced antimicrobial

Chunxiang Hou1, Andrew Su2, Patrick Combs3

  • 1Department of Entomology and Plant Pathology, Oklahoma State University, Stillwater, OK, 74078, USA.

Insect Biochemistry and Molecular Biology
|April 6, 2026
PubMed

Insights

Insect immune peptides (AMPs) are activated by specific enzymes (DPP4s). This study reveals how DPP4A and DPP4B activate moricins, enhancing their antimicrobial potency and stabilizing their structure for innate immunity.

Area of Science:

  • Biochemistry
  • Insect Immunity
  • Molecular Biology

Background:

  • Antimicrobial peptides (AMPs) are crucial for innate immunity, directly killing microbes.
  • In insects, α-helical AMPs like moricins are synthesized as inactive precursors.
  • Activation of these precursors by dipeptidyl peptidase IVs (DPP4s) is essential but poorly understood.

Purpose of the Study:

  • To identify and characterize two DPP4 enzymes (DPP4A and DPP4B) from Manduca sexta.
  • To investigate the biochemical basis and functional consequences of DPP4-mediated AMP activation.
  • To elucidate the structural changes in AMPs upon proteolytic processing.

Main Methods:

  • Gene cloning and recombinant protein expression in Sf9 cells.
  • Biochemical characterization of DPP4A and DPP4B enzyme kinetics and optimal pH.
  • Expression profiling via immune challenge and analysis of developmental stages.
  • Analysis of pro-moricin-6 activation and antimicrobial activity assays.
  • Structural determination using solution NMR and molecular dynamics simulations.

Main Results:

  • DPP4A and DPP4B exhibit distinct catalytic properties and expression patterns.
  • Both enzymes efficiently process pro-moricin-6, increasing its antimicrobial activity ~10-fold.
  • Activation involves sequential cleavage of two Xaa-Pro dipeptides.
  • Proteolytic processing stabilizes a continuous α-helix in mature moricin-6, enhancing membrane interaction and antimicrobial function.

Conclusions:

  • DPP4A and DPP4B play significant roles in insect immunity, digestion, and development.
  • Limited proteolysis by DPP4s precisely regulates AMP structure and potency.
  • This mechanism optimizes α-helical AMPs for effective innate immune defense.
Keywords:
DPP4Insect immunityMolecular dynamics simulationNMR structureProteolytic activationS8 serine proteaseantimicrobial peptide

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