Structural basis of RIP2 activation and signaling

  • Nat Commun. 2018 Nov 26;9(1):4993. doi: 10.1038/s41467-018-07447-9.
Qin Gong  1  2 ,  Ziqi Long  1  2 ,  Franklin L Zhong  3 ,  Daniel Eng Thiam Teo  3 ,  Yibo Jin  1  2 ,  Zhan Yin  1  2  4 ,  Zhao Zhi Boo  1  2 ,  Yaming Zhang  1  2 ,  Jiawen Zhang  1  2 ,  Renliang Yang  1  2 ,  Shashi Bhushan  1  2 ,  Bruno Reversade  3  5  6  7  8 ,  Zongli Li  9 ,  Bin Wu  10  11
Affiliations
  • 1. School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
  • 2. NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore.
  • 3. Institute of Medical Biology, A*STAR, Singapore, Singapore.
  • 4. Medical Research Council, University of Cambridge, Cambridge, CB2 0XY, UK.
  • 5. Department of Paediatrics, National University of Singapore, Singapore, Singapore.
  • 6. Institute of Molecular and Cellular Biology, A*STAR, Singapore, Singapore.
  • 7. Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
  • 8. Reproductive Biology Laboratory, Academic Medical Center (AMC), Amsterdam-Zuidoost, The Netherlands.
  • 9. Department of Biological Chemistry & Molecular Pharmacology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 10. School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore. [email protected].
  • 11. NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore. [email protected].
PMID: 30478312 DOI: 10.1038/s41467-018-07447-9
Abstract

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.