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Structural and functional studies of NOD1

Abstract : NOD1 is a cytosolic signaling host pattern-recognition receptor playing a crucial role in innate immunity. It regulates pro-inflammatory pathways by mediating the activation of the nuclear factor NF-kB via its downstream effector RICK following the recognition of a specific bacterial ligand. RICK is recruited by NOD1 through a CARD-CARD interaction. The goal of this thesis was to determine the structural basis of this process. NOD1 CARD was cloned, expressed and purified at the Grenoble EMBL Outstation. Its structure was determined by nuclear magnetic resonance at the IBS in Grenoble. It is generally similar to other CARDs of known structure, consisting of six tightly packed a-helices, although the conformation of some of the inter-helical loops and the orientation and length of the last helix are unusual. Mutations in the CARD domains of both NOD1 and RICK full-length proteins were made in order to define residues important for CARD-CARD interaction. Co-immunoprecipitation of cell lysates and NF-kB activation assays were performed at the University of Michigan Medical School. The results suggest that the interaction is primarily electrostatic and dependent on a patch of three acidic residues on NOD1 CARD (E53, D54, and E56) and three basic residues on RICK CARD (R444, R483 and R488). In addition, two amino acids L44 and I57, located in or close to the acidic patch of NOD1 were found to affect NOD1 signaling. These could be involved in the precise formation of a functional CARD-CARD interaction, or they could interact with other regions of RICK than the CARD domain.
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https://tel.archives-ouvertes.fr/tel-00100340
Contributor : Florence Manon <>
Submitted on : Tuesday, September 26, 2006 - 11:32:52 AM
Last modification on : Thursday, March 5, 2020 - 3:15:56 PM
Long-term archiving on: : Tuesday, April 6, 2010 - 1:12:58 AM

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  • HAL Id : tel-00100340, version 1

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Florence Manon. Structural and functional studies of NOD1. Biomolecules [q-bio.BM]. Université Joseph-Fourier - Grenoble I, 2006. English. ⟨tel-00100340⟩

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