Membrane Association Dictates Ligand Specificity for
the Innate Immune Receptor NOD2
Version 2 2018-07-14, 13:13
Version 1 2017-07-25, 13:20
Posted on 2018-07-14 - 13:13
The
human gut must regulate its immune response to resident and
pathogenic bacteria, numbering in the trillions. The peptidoglycan
component of the bacterial cell wall is a dense and rigid structure
that consists of polymeric carbohydrates and highly cross-linked peptides
which offers protection from the host and surrounding environment.
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2),
a human membrane-associated innate immune receptor found in the gut
epithelium and mutated in an estimated 30% of Crohn’s disease
patients, binds to peptidoglycan fragments and initiates an immune
response. Using a combination of chemical synthesis, advanced analytical
assays, and protein biochemistry, we tested the binding of a variety
of synthetic peptidoglycan fragments to wild-type (WT)-NOD2. Only
when the protein was presented in the native membrane did binding
measurements correlate with a NOD2-dependent nuclear factor kappa-light-chain-enhancer
of activated B cells (NF-κB) response, supporting the hypothesis
that the native-membrane environment confers ligand specificity to
the NOD2 receptor for NF-κB signaling. While N-acetyl-muramyl dipeptide (MDP) has been thought to be the minimal
peptidoglycan fragment necessary to activate a NOD2-dependent immune
response, we found that fragments with and without the dipeptide moiety
are capable of binding and activating a NOD2-dependent
NF-κB response, suggesting that the carbohydrate moiety of the
peptidoglycan fragments is the minimal functional epitope. This work
highlights the necessity of studying NOD2-ligand binding in systems
that resemble the receptor’s natural environment, as the cellular
membrane and/or NOD2 interacting partners appear to play a crucial
role in ligand binding and in triggering an innate immune response.
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Schaefer, Amy K.; Melnyk, James E.; Baksh, Michael M.; Lazor, Klare M.; Finn, M. G.; Grimes, Catherine Leimkuhler (2017). Membrane Association Dictates Ligand Specificity for
the Innate Immune Receptor NOD2. ACS Publications. Collection. https://doi.org/10.1021/acschembio.7b00469
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AUTHORS (6)
AS
Amy K. Schaefer
JM
James E. Melnyk
MB
Michael M. Baksh
KL
Klare M. Lazor
MF
M. G. Finn
CG
Catherine Leimkuhler Grimes