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PMID:15882992

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Citation

Lu, C, Wang, A, Wang, L, Dorsch, M, Ocain, TD and Xu, Y (2005) Nucleotide binding to CARD12 and its role in CARD12-mediated caspase-1 activation. Biochem. Biophys. Res. Commun. 331:1114-9

Abstract

CARD12 (Ipaf/Clan) is an important regulator of caspase-1 activation. It belongs to the family of the nucleotide-binding site and leucine-rich repeat (NBS-LRR) proteins. The NBS domain of the NBS-LRR proteins contains putative ATP/GTPase-specific P-loop and Mg2+-binding site motifs. However, the nucleotide-binding properties and the function of the NBS domain are unknown. We developed a nucleotide-binding assay and investigated nucleotide binding to CARD12. We find that the NBS domain of CARD12 contains a nucleotide-binding pocket with specificity for ATP/dATP. A point mutation in the P-loop (K175R) of the NBS domain abolishes ATP/dATP binding. We further demonstrate that the nucleotide-binding site is required for CARD12-mediated caspase-1 activation. CARD12 self-association and association with procaspase-1 in transfected cells were markedly decreased by the P-loop mutation K175R. Furthermore, the P-loop mutation greatly reduced caspase-1 activation-dependent proIL-1beta processing. Thus, CARD12 function is dependent on the nucleotide-binding site. Our data provide insights into the molecular mechanisms of CARD12-mediated caspase-1 activation.

Links

PubMed Online version:10.1016/j.bbrc.2005.04.027

Keywords

Adenosine Triphosphate/metabolism; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism; Calcium-Binding Proteins/physiology; Caspase 1/metabolism; Enzyme Activation; Point Mutation; Protein Binding

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CASP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPP4

F

Seeded From UniProt

complete

HUMAN:CASP1

enables

GO:0004197: cysteine-type endopeptidase activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:Q9NPP4

F

Seeded From UniProt

complete

HUMAN:CASP1

involved_in

GO:0140448: signaling receptor ligand precursor processing

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:Q9NPP4

P

Seeded From UniProt

complete

HUMAN:CASP1

involved_in

GO:0140447: cytokine precursor processing

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:Q9NPP4

P

  • has_input:(UniProtKB:P01584)

Seeded From UniProt

complete

HUMAN:NLRC4

involved_in

GO:0010954: positive regulation of protein processing

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:P29466

P

Seeded From UniProt

complete

HUMAN:NLRC4

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPP4

F

Seeded From UniProt

complete

HUMAN:NLRC4

enables

GO:0061133: endopeptidase activator activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:P29466

F

Seeded From UniProt

complete

HUMAN:NLRC4

enables

GO:0089720: caspase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29466

F

Seeded From UniProt

complete

HUMAN:NLRC4

involved_in

GO:0097202: activation of cysteine-type endopeptidase activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:P29466

P

Seeded From UniProt

complete

HUMAN:NLRC4

involved_in

GO:0032731: positive regulation of interleukin-1 beta production

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P10749,UniProtKB:P29466

P

Seeded From UniProt

complete

HUMAN:NLRC4

enables

GO:0000287: magnesium ion binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NLRC4

GO:0097202: activation of cysteine-type endopeptidase activity

ECO:0000315:

P

Fig 6

complete
CACAO 11414

HUMAN:NLRC4

enables

GO:0005524: ATP binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NLRC4

involved_in

GO:0050702: interleukin-1 beta secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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