Structural Basis of RIP2 Activation and Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Nov 28

PMID 30478312

Citations 36

Authors

Qin Gong

Ziqi Long

Franklin L Zhong

Daniel Eng Thiam Teo

Yibo Jin

Zhan Yin

Zhao Zhi Boo

Yaming Zhang

Jiawen Zhang

Renliang Yang

Shashi Bhushan

Bruno Reversade

Zongli Li

Bin Wu

Affiliations

Soon will be listed here.

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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