PUBLICATION
ZIPK: A Unique Case of Murine-Specific Divergence of a Conserved Vertebrate Gene
- Authors
- Shoval, Y., Pietrokovski, S., and Kimchi, A.
- ID
- ZDB-PUB-071029-6
- Date
- 2007
- Source
- PLoS Genetics 3(10): e180 (Journal)
- Registered Authors
- Keywords
- Sequence alignment, Multiple alignment calculation, Sequence databases, Phosphorylation, Rodents, Zebrafish, Rats, Protein structure comparison
- MeSH Terms
-
- Animals
- Apoptosis
- Apoptosis Regulatory Proteins/metabolism
- Apoptosis Regulatory Proteins/physiology*
- Calcium-Calmodulin-Dependent Protein Kinases/metabolism
- Calcium-Calmodulin-Dependent Protein Kinases/physiology*
- Conserved Sequence
- Cytoplasm/metabolism
- Death-Associated Protein Kinases
- Evolution, Molecular
- Humans
- Mice
- Mutation
- Phosphorylation
- Phylogeny
- Rats
- Species Specificity
- Zebrafish
- PubMed
- 17953487 Full text @ PLoS Genet.
Citation
Shoval, Y., Pietrokovski, S., and Kimchi, A. (2007) ZIPK: A Unique Case of Murine-Specific Divergence of a Conserved Vertebrate Gene. PLoS Genetics. 3(10):e180.
Abstract
Zipper interacting protein kinase (ZIPK, also known as death-associated protein kinase 3 [DAPK3]) is a Ser/Thr kinase that functions in programmed cell death. Since its identification eight years ago, contradictory findings regarding its intracellular localization and molecular mode of action have been reported, which may be attributed to unpredicted differences among the human and rodent orthologs. By aligning the sequences of all available ZIPK orthologs, from fish to human, we discovered that rat and mouse sequences are more diverged from the human ortholog relative to other, more distant, vertebrates. To test experimentally the outcome of this sequence divergence, we compared rat ZIPK to human ZIPK in the same cellular settings. We found that while ectopically expressed human ZIPK localized to the cytoplasm and induced membrane blebbing, rat ZIPK localized exclusively within nuclei, mainly to promyelocytic leukemia oncogenic bodies, and induced significantly lower levels of membrane blebbing. Among the unique murine (rat and mouse) sequence features, we found that a highly conserved phosphorylation site, previously shown to have an effect on the cellular localization of human ZIPK, is absent in murines but not in earlier diverging organisms. Recreating this phosphorylation site in rat ZIPK led to a significant reduction in its promyelocytic leukemia oncogenic body localization, yet did not confer full cytoplasmic localization. Additionally, we found that while rat ZIPK interacts with PAR-4 (also known as PAWR) very efficiently, human ZIPK fails to do so. This interaction has clear functional implications, as coexpression of PAR-4 with rat ZIPK caused nuclear to cytoplasm translocation and induced strong membrane blebbing, thus providing the murine protein a possible adaptive mechanism to compensate for its sequence divergence. We have also cloned zebrafish ZIPK and found that, like the human and unlike the murine orthologs, it localizes to the cytoplasm, and fails to bind the highly conserved PAR-4 protein. This further supports the hypothesis that murine ZIPK underwent specific divergence from a conserved consensus. In conclusion, we present a case of species-specific divergence occurring in a specific branch of the evolutionary tree, accompanied by the acquisition of a unique protein-protein interaction that enables conservation of cellular function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping