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PMID:11076957

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Citation

Hlaing, T, Guo, RF, Dilley, KA, Loussia, JM, Morrish, TA, Shi, MM, Vincenz, C and Ward, PA (2001) Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins. J. Biol. Chem. 276:9230-8

Abstract

We report the deduced amino acid sequences of two alternately spliced isoforms, designated DEFCAP-L and -S, that differ in 44 amino acids and encode a novel member of the mammalian Ced-4 family of apoptosis proteins. Similar to the other mammalian Ced-4 proteins (Apaf-1 and Nod1), DEFCAP contains a caspase recruitment domain (CARD) and a putative nucleotide binding domain, signified by a consensus Walker's A box (P-loop) and B box (Mg(2+)-binding site). Like Nod1, but different from Apaf-1, DEFCAP contains a putative regulatory domain containing multiple leucine-rich repeats (LRR). However, a distinguishing feature of the primary sequence of DEFCAP is that DEFCAP contains at its NH(2) terminus a pyrin-like motif and a proline-rich sequence, possibly involved in protein-protein interactions with Src homology domain 3-containing proteins. By using in vitro coimmunoprecipitation experiments, both long and short isoforms were capable of strongly interacting with caspase-2 and exhibited a weaker interaction with caspase-9. Transient overexpression of full-length DEFCAP-L, but not DEFCAP-S, in breast adenocarcinoma cells MCF7 resulted in significant levels of apoptosis. In vitro death assays with transient overexpression of deletion constructs of both isoforms using beta-galactosidase as a reporter gene in MCF7 cells suggest the following: 1) the nucleotide binding domain may act as a negative regulator of the killing activity of DEFCAP; 2) the LRR/CARD represents a putative constitutively active inducer of apoptosis; 3) the killing activity of LRR/CARD is inhibitable by benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone and to a lesser extent by Asp-Glu-Val-Asp (OMe)-fluoromethyl ketone; and 4) the CARD is critical for killing activity of DEFCAP. These results suggest that DEFCAP is a novel member of the mammalian Ced-4 family of proteins capable of inducing apoptosis, and understanding its regulation may elucidate the complex nature of the mammalian apoptosis-promoting machinery.

Links

PubMed Online version:10.1074/jbc.M009853200

Keywords

Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Apoptosis; Apoptosis Regulatory Proteins; Base Sequence; Caenorhabditis elegans Proteins; Calcium-Binding Proteins/chemistry; Calcium-Binding Proteins/genetics; Carrier Proteins/chemistry; Carrier Proteins/genetics; Cell Line; Chromosome Mapping; Cloning, Molecular; DNA, Complementary; Helminth Proteins/chemistry; Helminth Proteins/genetics; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Isoforms/genetics; RNA, Messenger/genetics; Recombinant Fusion Proteins/metabolism; Sequence Homology, Amino Acid

Significance

Annotations

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

HUMAN:CASP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9C000

F

Seeded From UniProt

complete

HUMAN:NLRP1

enables

GO:0008656: cysteine-type endopeptidase activator activity involved in apoptotic process

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NLRP1

involved_in

GO:0006915: apoptotic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLRP1

involved_in

GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLRP1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42575

F

Seeded From UniProt

complete

HUMAN:NALP1

enables

GO:0008656: cysteine-type endopeptidase activator activity involved in apoptotic process

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NALP1

involved_in

GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NALP1

involved_in

GO:0006915: apoptotic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NALP1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42575

F

Seeded From UniProt

complete

HUMAN:CASP2

enables

GO:0019899: enzyme binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q9C000

F

Seeded From UniProt

complete


See also

References

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