Crystal structure of NOD2 and its implications in human disease

Sakiko Maekawa, Umeharu Ohto, Takuma Shibata, Kensuke Miyake and Toshiyuki Shimizu ()
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Sakiko Maekawa: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Umeharu Ohto: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Takuma Shibata: The Institute of Medical Science, The University of Tokyo
Kensuke Miyake: The Institute of Medical Science, The University of Tokyo
Toshiyuki Shimizu: Graduate School of Pharmaceutical Sciences, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a member of the NOD-like receptors family, are crucial for innate immune responses. Mutations of NOD2 have been associated with chronic inflammatory disorders such as Crohn’s disease (CD), Blau syndrome (BS) and early-onset sarcoidosis (EOS), but little is known about its signalling mechanism and the role it plays in these diseases. Here, we report the crystal structure of rabbit NOD2 in an ADP-bound state. The structure reveals an inactive closed conformation in which the subdomains in the NOD domain are closely packed by ADP-mediated and inter-domain interactions. Mapping of the BS- or EOS-associated gain-of-function mutations reveals that most of these mutations are located in the NOD subdomain interfaces, and are likely to disrupt the inner domain interactions, facilitating a conformational change to the active form. Conversely, mutations associated with CD are distributed throughout the protein, some of which may affect oligomer formation and ligand binding.

Date: 2016
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DOI: 10.1038/ncomms11813

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