2. Academic Validation
  3. NLRP6 self-assembles into a linear molecular platform following LPS binding and ATP stimulation

NLRP6 self-assembles into a linear molecular platform following LPS binding and ATP stimulation

  • Sci Rep. 2020 Jan 13;10(1):198. doi: 10.1038/s41598-019-57043-0.
Fangwei Leng 1 2 3,  Hang Yin 2 4,  Siying Qin 2,  Kai Zhang 1,  Yukun Guan 5,  Run Fang 5,  Honglei Wang 6,  Guohui Li 6,  Zhengfan Jiang 5,  Fei Sun 1,  Da-Cheng Wang 7,  Can Xie 8 9
Affiliations

Affiliations

  • 1 National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 State Key Laboratory of Membrane Biology, Laboratory of Molecular Biophysics, School of Life Sciences, Peking University, Beijing, 100871, China.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
  • 5 State Key Laboratory of Protein and Plant Gene Research, Peking-Tsinghua Center for Life Sciences, College of Life Sciences, Peking University, Beijing, 100871, China.
  • 6 Laboratory of Molecular Modeling and Design, State Key Lab of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Liaoning, 116023, China.
  • 7 National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 8 State Key Laboratory of Membrane Biology, Laboratory of Molecular Biophysics, School of Life Sciences, Peking University, Beijing, 100871, China. [email protected].
  • 9 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
PMID: 31932628 DOI: 10.1038/s41598-019-57043-0
Abstract

NOD-like receptors (NLRs) localize in the cytosol to recognize intracellular pathogen products and initialize the innate immune response. However, the ligands and ligand specificity of many NLRs remain unclear. One such NLR, NLRP6, plays an important role in maintaining intestinal homeostasis and protecting against various intestinal diseases such as colitis and intestinal tumorigenesis. Here, we show that the major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS), binds NLRP6 directly and induces global conformational change and dimerization. Following stimulation by ATP, the NLRP6 homodimer can further assemble into a linear molecular platform, and ASC is recruited to form higher molecular structures, indicative of a step-by-step activation mechanism. Our study sheds LIGHT on the mystery of LPS-induced inflammasome initiation, reveals the architecture and structural basis of potential pre-inflammasome, and suggests a novel molecular assembly pattern for immune receptors.

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