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LPS binding caspase activation and recruitment domains (CARDs) are bipartite lipid binding modules

Anh B Cao1, Pascal Devant1, Chengliang Wang2

  • 1Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Science Advances
|March 7, 2025
PubMed

Insights

Caspase-11

Area of Science:

  • Innate immunity
  • Molecular biology
  • Structural biology

Background:

  • Caspase-11 acts as a pattern recognition receptor (PRR) in innate immunity.
  • It recognizes cytosolic bacterial lipopolysaccharides (LPS) and eukaryotic (self) lipids via its caspase activation and recruitment domain (CARD).
  • The mechanisms for detecting self- and non-self lipids by caspase-11 remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which the caspase-11 CARD interacts with self- and non-self lipids.
  • To determine if common or distinct binding regions within the CARD are involved.
  • To engineer a novel LPS-binding domain based on these findings.

Main Methods:

  • Biochemical assays
  • Computational modeling
  • Cell-based assays
  • Structural analysis of CARD domains

Main Results:

  • The caspase-11 CARD functions as a bipartite lipid-binding module.
  • Specific regions within the CARD bind to phosphate groups and long acyl chains of both self- and non-self lipids.
  • Self-lipid binding is conserved across various caspase-11 homologs and orthologs.
  • A de novo LPS-binding domain was engineered using an ancestral CARD-like domain from *Amphilophus citrinellus*.

Conclusions:

  • The findings elucidate the molecular basis of LPS recognition by caspase-11.
  • Caspase-11 utilizes distinct regions for binding self- and non-self lipids, revealing a bipartite mechanism.
  • This study highlights the conserved nature of self-lipid recognition and provides a framework for engineering novel lipid-binding domains.

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