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Nanoscale Mechanical Force Primes NOD1-LRR for Efficient Pathogen Recognition.

Yang Ye1, Yong Zhang2,3, Jing Li4

  • 1Kidney Disease Center of the First Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.

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NOD1 acts as a nanomechanical sensor, concentrating forces to detect bacterial ligands. This mechanochemical coupling enables rapid and precise innate immune activation against pathogens.

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Area of Science:

  • Innate Immunity
  • Molecular Mechanobiology
  • Nanobiology

Background:

  • Cytosolic innate immune receptors, like NOD1, detect pathogens biochemically.
  • The ability of these receptors to sense physical cues is largely unknown.
  • Understanding mechanotransduction in innate immunity is crucial for pathogen detection.

Purpose of the Study:

  • To investigate if NOD1 functions as a nanomechanical sensor.
  • To elucidate the role of physical forces in NOD1-mediated pathogen recognition.
  • To establish a new paradigm for cytosolic pathogen detection.

Main Methods:

  • Piconewton-resolution single-molecule force spectroscopy.
  • Molecular dynamics simulations.
  • Structural modeling of the NOD1 receptor.

Main Results:

  • NOD1's LRR domain acts as a mechanical force concentrator.
  • Physiologically relevant forces prime NOD1 for conformational changes.
  • Force-induced priming enhances binding affinity and sensitivity to bacterial ligand iE-DAP.
  • Demonstrated mechanochemical coupling in NOD1 function.

Conclusions:

  • NOD1 is an active nanomechanical sensor, not a passive detector.
  • Mechanochemical coupling enables rapid and spatially restricted immune activation.
  • Force-sensing LRR domains represent a generalizable design principle in nanobiology and innate immunity.