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.

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