Three-dimensional structure of the NLRP7 pyrin domain: insight into pyrin-pyrin-mediated effector domain signaling in innate immunity.
The innate immune system provides an initial line of defense against infection. Nucleotide-binding domain- and leucine-rich repeat-containing protein (NLR or (NOD-like)) receptors play a critical role in the innate immune response by surveying the cytoplasm for traces of intracellular invaders and endogenous stress signals. NLRs themselves are multi-domain proteins. Their N-terminal effector domains (typically a pyrin or caspase activation and recruitment domain) are responsible for driving downstream signaling and initiating the formation of inflammasomes, multi-component complexes necessary for cytokine activation. However, the currently available structures of NLR effector domains have not yet revealed the mechanism of their differential modes of interaction. Here, we report the structure and dynamics of the N-terminal pyrin domain of NLRP7 (NLRP7 PYD) obtained by NMR spectroscopy. The NLRP7 PYD adopts a six-alpha-helix bundle death domain fold. A comparison of conformational and dynamics features of the NLRP7 PYD with other PYDs showed distinct differences for helix alpha3 and loop alpha2-alpha3, which, in NLRP7, is stabilized by a strong hydrophobic cluster. Moreover, the NLRP7 and NLRP1 PYDs have different electrostatic surfaces. This is significant, because death domain signaling is driven by electrostatic contacts and stabilized by hydrophobic interactions. Thus, these results provide new insights into NLRP signaling and provide a first molecular understanding of inflammasome formation.
Pinheiro
Anderson S
AS
Departments of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, Austria.
Proell
Martina
M
Department of Molecular Biology, University of Salzburg, A-5020 Salzburg, Austria.
Eibl
Clarissa
C
Department of Molecular Biology, University of Salzburg, A-5020 Salzburg, Austria.
Page
Rebecca
R
Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, Austria.
Schwarzenbacher
Robert
R
Department of Molecular Biology, University of Salzburg, A-5020 Salzburg, Austria.
Peti
Wolfgang
W
Departments of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, Austria. Electronic address: wolfgang_peti@brown.edu.
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000071198:Pyrin; D055672:Static Electricity; D013329:Structure-Activity Relationship
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; C502448:NLRP7 protein, human; D000071198:Pyrin