ME10, a Novel Caspase Recruitment Domain-containing Proapoptotic Molecule

Minhong Yan,James Lee,Sarah Schilbach,Audrey Goddard,Vishva Dixit

doi:10.1074/jbc.274.15.10287

Minhong Yan, James Lee + Show 3 more

Open Access

https://doi.org/10.1074/jbc.274.15.10287

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Abstract

Apoptotic signaling is mediated by homophilic interactions between conserved domains present in components of the death pathway. The death domain, death effector domain, and caspase recruitment domain (CARD) are examples of such interaction motifs. We have identified a novel mammalian CARD-containing adaptor molecule termed mE10 (mammalian E10). The N-terminal CARD of mE10 exhibits significant homology (47% identity and 64% similarity) to the CARD of a gene from Equine Herpesvirus type 2. The C-terminal region is unique. Overexpression of mE10 in MCF-7 human breast carcinoma cells induces apoptosis. Mutational analysis indicates that CARD-mediated mE10 oligomerization is essential for killing activity. The C terminus of mE10 bound to the zymogen form of caspase-9 and promoted its processing to the active dimeric species. Taken together, these data suggest a model where autoproteolytic activation of pro-caspase-9 is mediated by mE10-induced oligomerization.

Highlights

The core components of the death pathway as revealed by genetic analysis of the nematode Caenorhabditis elegans are remarkably conserved through evolution [1] to a much greater degree of complexity in mammals [2]
This is reflected in the fact that, except for CED-4, multiple homologs of each of the core components are found in mammals
Worm CED-4 and its mammalian homolog Apaf-1 function to promote the autoproteolytic activation of downstream effector death proteases termed caspases [3, 4]

Summary

Introduction

The core components of the death pathway as revealed by genetic analysis of the nematode Caenorhabditis elegans are remarkably conserved through evolution [1] to a much greater degree of complexity in mammals [2]. Worm CED-4 and its mammalian homolog Apaf-1 function to promote the autoproteolytic activation of downstream effector death proteases termed caspases [3, 4]. Three such interaction motifs have been defined: the death domain, the death effector domain [9], and the caspase recruitment domain (CARD) [10].1 All contain a conserved stretch of about 90 amino acids in length.

Results

Conclusion