Structural basis for specific flagellin recognition by the NLR protein NAIP5

Area of Science:

• Immunology
• Structural Biology
• Microbiology

Background:

• Nucleotide-binding domain- and leucine-rich repeat (LRR)-containing proteins (NLRs) are crucial intracellular immune receptors.
• The precise mechanisms by which NLRs recognize their ligands are not fully understood.

Purpose of the Study:

• To elucidate the structural basis of ligand recognition by NLR proteins NAIP5 and NLRC4.
• To understand how NLRs discriminate between different bacterial flagellins.

Main Methods:

• Cryo-electron microscopy was used to determine the structure of a flagellin derivative bound to NAIP5 and NLRC4 at 4.28 Å resolution.
• Biochemical assays were performed to support structural findings.

Main Results:

• The structure revealed a flagellin derivative forming parallel helices that interact with NAIP5 domains (BIR1, LRR).
• Flagellin binding stabilizes the active conformation of NAIP5 by nearly complete burial.
• A sterically constrained pocket anchors the flagellin C-terminus, suggesting a mechanism for flagellin discrimination.

Conclusions:

• The study provides a molecular understanding of how NLRs perceive bacterial flagellin ligands.
• Structural insights into NAIP5-flagellin complex formation illuminate NLR-mediated innate immune signaling pathways.