Monomer/dimer transition of the caspase-recruitment domain of human Nod1

Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Biochemistry (Impact Factor: 3.19). 03/2008; 47(5):1319-25. DOI: 10.1021/bi7016602
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Naohiro Inohara, Apr 07, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: E3 ligases mediate the covalent attachment of ubiquitin to target proteins thereby enabling ubiquitin-dependent signaling. Unraveling how E3 ligases are regulated is important because miscontrolled ubiquitylation can lead to disease. Cellular inhibitor of apoptosis (cIAP) proteins are E3 ligases that modulate diverse biological processes such as cell survival, proliferation, and migration. Here, we have solved the structure of the caspase recruitment domain (CARD) of cIAP1 and identified that it is required for cIAP1 autoregulation. We demonstrate that the CARD inhibits activation of cIAP1's E3 activity by preventing RING dimerization, E2 binding, and E2 activation. Moreover, we show that the CARD is required to suppress cell proliferation and migration. Further, CARD-mediated autoregulation is also necessary to maximally suppress caspase-8-dependent apoptosis and vascular tree degeneration in vivo. Taken together, our data reveal mechanisms by which the E3 ligase activity of cIAP1 is controlled, and how its deregulation impacts on cell proliferation, migration and cell survival.
    Molecular cell 06/2011; 42(5):569-83. DOI:10.1016/j.molcel.2011.04.008 · 14.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammasomes are crucial actors of the innate immunity. They consist of cytoplasmic multiprotein complexes controlling the biological activities of the inflammatory cytokines IL-1β and IL-18. Inflammasome assembly depends on protein domain interactions. In this chapter, we focus on the biochemical aspects characterizing the components of the inflammasomes and their assembly into a high molecular weight proteolytic complex.
    01/1970: pages 1-16;
  • [Show abstract] [Hide abstract]
    ABSTRACT: This communication presents works of research achieved at the DIAM/IUSPIM on the dimensioning and functional tolerancing of the complex mechanical systems aided by computer in CAD/CAM systems. The dimensioning and functional tolerancing processing has been formalized in using the principle of the envelope. It integrates clearance and contact evolution of mechanical systems in functioning. It integrates production constraints associated by designer to each mechanical part. It allows one to research and manage manufacturing dimension chain conflicts and distribute tolerances. The intervention of the user in the processing insures the tolerancing adaptation to each particular mechanical system. An autonomous computer tool called “CotAO” was made to achieve dimensioning and functional tolerancing processing. The efficiency and the attractiveness of the processing will be obtained by “CotAO” interfacing with a CAD system. This interfacing necessitates, often, the achieving of an adaptation module of the host CAD system. The present “CotAO” interfacing is being made with the Autocad software. The use of such tools contributes to the tolerancing optimization and to the improvement of the mechanical part definition quality. It should appreciably shorten the time necessary to define manufacturing dimensions. It would lead to evolution in the design-manufacturing cycle to a better CAD/CAM system integration
    Emerging Technologies and Factory Automation, 1995. ETFA '95, Proceedings., 1995 INRIA/IEEE Symposium on; 11/1995