Structural basis of RIP2 activation and signaling

• Main Authors: Gong, Qin, Long, Ziqi, Zhong, Franklin L., Teo, Daniel Eng Thiam, Jin, Yibo, Yin, Zhan, Boo, Zhao Zhi, Zhang, Yaming, Zhang, Jiawen, Yang, Renliang, Bhushan, Shashi, Reversade, Bruno, Li, Zongli, Wu, Bin
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2019
• Subjects: DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/89110; http://hdl.handle.net/10220/47668
• Institution: Nanyang Technological University

Signals arising from bacterial infections are detected by pathogen recognition receptors (PRRs) and are transduced by specialized adapter proteins in mammalian cells. The Receptor-interacting-serine/threonine-protein kinase 2 (RIPK2 or RIP2) is such an adapter protein that is critical for signal propagation of the Nucleotide-binding-oligomerization-domain-containing proteins 1/2 (NOD1 and NOD2). Dysregulation of this signaling pathway leads to defects in bacterial detection and in some cases autoimmune diseases. Here, we show that the Caspase-activation-and-recruitment-domain (CARD) of RIP2 (RIP2-CARD) forms oligomeric structures upon stimulation by either NOD1-CARD or NOD2-2CARD. We reconstitute this complex, termed the RIPosome in vitro and solve the cryo-EM filament structure of the active RIP2-CARD complex at 4.1 Å resolution. The structure suggests potential mechanisms by which CARD domains from NOD1 and NOD2 initiate the oligomerization process of RIP2-CARD. Together with structure guided mutagenesis experiments at the CARD-CARD interfaces, we demonstrate molecular mechanisms how RIP2 is activated and self-propagating such signal.