Monomer/Dimer Transition of the Caspase-Recruitment Domain of Human Nod1 † , ‡

Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Biochemistry (Impact Factor: 3.02). 03/2008; 47(5):1319-25. DOI: 10.1021/bi7016602
Source: PubMed


Nod1 is an essential cytoplasmic sensor for bacterial peptidoglycans in the innate immune system. The caspase-recruitment domain of Nod1 (Nod1_CARD) is indispensable for recruiting a downstream kinase, receptor-interacting protein 2 (RIP2), that activates nuclear factor-kappaB (NF-kappaB). The crystal structure of human Nod1_CARD at 1.9 A resolution reveals a novel homodimeric conformation. Our structural and biochemical analysis shows that the homodimerization of Nod1_CARD is achieved by swapping the H6 helices at the carboxy termini and stabilized by forming an interchain disulfide bond between the Cys39 residues of the two monomers in solution and in the crystal. In addition, we present experimental evidence for a pH-sensitive conformational change of Nod1_CARD. Our results suggest that the pH-sensitive monomer/dimer transition is a unique molecular property of Nod1_CARD.

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Available from: Naohiro Inohara, Apr 07, 2015
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    • "Here we report the crystal structure of a complex of NOD1 CARD and Ub. NOD1 CARD is present as a domain-swapped homodimer, similar to previously reported structures [21], [22], while two Ub monomers interact in a conformation similar to that of Lys48-linked di-Ub [23]. We discuss the implications of this structure with regard to how NOD1 and other Ub-binding proteins may recognize Ub in vivo. "
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    ABSTRACT: The Caspase Recruitment Domain (CARD) from the innate immune receptor NOD1 was crystallized with Ubiquitin (Ub). NOD1 CARD was present as a helix-swapped homodimer similar to other structures of NOD1 CARD, and Ub monomers formed a homodimer similar in conformation to Lys48-linked di-Ub. The interaction between NOD1 CARD and Ub in the crystal was mediated by novel binding sites on each molecule. Comparisons of these sites to previously identified interaction surfaces on both molecules were made along with discussion of their potential functional significance.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "was submitted to the NetPhos 2.0 server [17] for the identification of potential serine, threonine and tyrosine phosphorylation sites. Solvent accessibility of residues in the monomeric [PDB: 2dbd] and dimeric [PDB: 2nz7] [18] forms of the NOD1 CARD was determined using ASAview [19]. Mammalian NOD1 orthologues were recovered from the NCBI non-redundant protein database using blastp (protein-protein BLAST) with human NOD1 [Genbank: AAD28350.1] "
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    ABSTRACT: Activation and signal transduction in the Nucleotide binding, leucine-rich repeat containing receptor (NLR) family needs to be tightly regulated in order to control the inflammatory response to exogenous and endogenous danger signals. Phosphorylation is a common cellular mechanism of regulation that has recently been shown to be important in signalling in another family of cytoplasmic pattern recognition receptors, the RIG-I like receptors. In addition, single nucleotide polymorphisms can alter receptor activity, potentially leading to dysfunction and/or a predisposition to inflammatory barrier diseases. We have computationally analysed the N-terminus of NOD1 and found seven theoretical phosphorylation sites in, or immediately before, the NOD1 Caspase Activation Domain (CARD). Two of these, serine 7 and tyrosine 49 are also found as rare polymorphisms in the African-American population and European-American populations respectively. Mutating serine 7 to either an aspartic acid or an asparagine to mimic the potential impact of phosphorylation or the polymorphism respectively did not affect the response of NOD1 to ligand-mediated NFkappaB signalling. The NOD1 polymorphism S7N does not interfere with receptor function in response to ligand stimulation.
    Full-text · Article · Mar 2014 · BMC Research Notes
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    • "This was suggested to mediate homodimerization of NOD1. Unfortunately, the presence of a disulfide bond between the molecules clouded the conclusions [18], [19]. The sixth helix of MALT1 CARD domain, in the crystalline state, also sits in its canonical position in another molecule, but not in a swapped dimer interaction. "
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    ABSTRACT: Mucosa-associated lymphoid tissue 1 (MALT1) plays an important role in the adaptive immune program. During TCR- or BCR-induced NF-κB activation, MALT1 serves to mediate the activation of the IKK (IκB kinase) complex, which subsequently regulates the activation of NF-κB. Aggregation of MALT1 is important for E3 ligase activation and NF-κB signaling. Unlike the isolated CARD or paracaspase domains, which behave as monomers, the tandem Ig-like domains of MALT1 exists as a mixture of dimer and tetramer in solution. High-resolution structures reveals a protein-protein interface that is stabilized by a buried surface area of 1256 Å(2) and contains numerous hydrogen and salt bonds. In conjunction with a second interface, these interactions may represent the basis of MALT1 oligomerization. The crystal structure of the tandem Ig-like domains reveals the oligomerization potential of MALT1 and a potential intermediate in the activation of the adaptive inflammatory pathway. This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
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