The 'unique key' feature of the Iap-binding motifs in RHG proteins.
The 'unique key' feature of the Iap-binding motifs in RHG proteins.
复制标题
RHG 蛋白中 Iap 结合基序的“独特关键”特征。
DOI：
10.1038/sj.cdd.4401637
复制
发表时间：
2005
影响因子：
12.4
通讯作者：
Zhou,L
中科院分区：
文献类型：
--
作者：
Zhou,L
Reaper, Hid, Grim, and Sickle are a group of fruit fly proteins that play pivotal roles in regulating apoptosis during development and in response to cytotoxic stimuli. A rich array of structure/function analysis indicated that two short motifs shared among these proteins contribute to their proapoptotic activity. So far, only in Drosophila melanogaster have all four proteins been identified. Taking advantage of genome sequence projects, we have identified orthologs of these proteins in several divergent Drosophila species. Comparison of the two motifs within and among the ortholog groups revealed a striking distinctiveness of the Iap-binding motif, which is characteristic of each group and is strictly conserved. This finding suggests that these proteins function as ‘unique’rather than ‘general’keys to unlock the inhibition of Iap on caspase activation. The GH3 motif, on the other hand, shows differential conservation. Together, these findings support the hypothesis that these proteins are not simply redundant, but each has a distinct role in regulating cell death. In the D. melanogaster genome, a region of about 300 kb on the third chromosome is essential for the proper execution of cell death. Mutant animals lacking this region are deficient for most developmental cell death and have dramatically impaired cell death response to cytotoxic stimuli. 1 Four of the genes harbored in this region, reaper (rpr), head involution defective (hid), grim, and sickle (skl), have proapoptotic function. Proteins encoded by these four genes, often referred to as the RHG proteins, have varying length and share little overall sequence similarity, except for two loosely linked short motifs. The lack of significant similarity also makes it difficult to judge whether they are paralogs resulting from duplication events, or alternatively, evolved from different protein lineages. The first motif is at the extreme N-terminal of the RHG proteins. It was termed RHG motif2 or IBM (Iap-binding motif). Structural and functional analysis indicated that IBM binds to Iap and thus releases its inhibition on the caspases. 3 The activation of caspases, a family of proteases, leads to cellular destruction through a morphological and biochemical ritual termed apoptosis. It has been demonstrated that short peptides harboring IBM are capable to induce cell death. The second motif shared by Reaper, Grim, and Sickle is termed trp-block, 2 or GH3 (Grim Helix 3). 4 It can induce cell death by itself in the absence of the IBM motif, with comparatively less efficiency. However, when both motifs are present, a cooperative effect in promoting cell death is observed. 4 Unlike the IBM motif, the functional mechanism of GH3 is less clear with some seemingly conflicting observations.To understand the evolution of these cell death genes, we sought to compare distant orthologs of these four proteins with a focus on the two functional motifs. Four Drosophila species were chosen for this comparison. D. yakuba (D. yaku) and D. pseudoobscura (D. pseu) are from the same subgenus (Sophophora) as D. melanogaster, and separated from D. melanogaster about 10 and 40 million years ago, respectively. 5 D. mojavensis (D. moja) and D. virilis (D. viri) belong to a different subgenus, Drosophila, which separated from Sophophora about 60–65 million years ago. Corresponding orthologs of the four Iap-antagonists were identified in all of the four selected genomes (Figure 1, and Supplementary material). Complete ORFs for these orthologs were identified with the only exception of hid in D. mojavensis. The genomic sequence of D. mojavensis has yet to be completed. However, strong homology between Hid and some segments of D. mojavensis genomic …
