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A novel group of multi-GAP-domain proteins.

ABSTRACT: The Rho GTPase-activating proteins (RhoGAPs) play an essential role in regulating various cellular processes. Rat tGAP1 is the first reported protein that has multiple GAP domains. It is exclusively expressed in male germ cells. However, tGAP1 does not possess GAP activities in vitro. No tGAP1 homology has been identified in other species. In this study, we searched the genomic databases and identified many genes whose protein products possess 2-4 GAP domains in rat, mouse and dog. These genes all showed sequence similarity to tGAP1. The rat tGAP gene loci all locate on chromosome 2 and are all expressed in testes in RT-PCR analysis. The mouse tGAP gene loci also clustered on chromosome 3 but RT-PCR analysis showed most are pseudogene loci. Multiple sequence alignment showed that many conserved residues of the "arginine finger" motif within the GAP domains of predicted tGAP proteins have mutated, suggesting that tGAP proteins do not possess GAP activity. We also elucidated the evolutionary relations among the rat tGAP genes. Based on the phylogenetic analysis data, we proposed that tGAP genes and Arhgap20 genes have a common ancestor.

SUBMITTER: Ruan Y

PROVIDER: S-EPMC5241158 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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A novel group of multi-GAP-domain proteins.

Ruan Yibing Y Sensen Christoph W CW van der Hoorn Frans A FA

Molecular reproduction and development 20081001 10

The Rho GTPase-activating proteins (RhoGAPs) play an essential role in regulating various cellular processes. Rat tGAP1 is the first reported protein that has multiple GAP domains. It is exclusively expressed in male germ cells. However, tGAP1 does not possess GAP activities in vitro. No tGAP1 homology has been identified in other species. In this study, we searched the genomic databases and identified many genes whose protein products possess 2-4 GAP domains in rat, mouse and dog. These genes a ...[more]

PMID: 18363199

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Project description:Peptide toxins isolated from animal venom secretions have proven to be useful pharmacological tools for probing the structure and function of a number of molecular receptors. Their molecular structures are stabilized by posttranslational formation of multiple disulfide bonds formed between sidechain thiols of cysteine residues, resulting in high thermal and chemical stability. Many of these peptides have been found to be potent modulators of ion channels, making them particularly influential in this field. Recently, several peptide toxins have been described that have an unusual tandem repeat organization, while also eliciting a unique pharmacological response toward ion channels. Most of these are two-domain peptide toxins from spider venoms, such as the double-knot toxin (DkTx), isolated from the Earth Tiger tarantula (Haplopelma schmidti). The unusual pharmacology of DkTx is its high avidity for its receptor (TRPV1), a property that has been attributed to a bivalent mode-of-action. DkTx has subsequently proven a powerful tool for elucidating the structural basis for the function of the TRPV1 channel. Interestingly, all tandem repeat peptides functionally characterized to date share this high avidity to their respective binding targets, suggesting they comprise an unrecognized structural class of peptides with unique structural features that result in a characteristic set of pharmacological properties. In this article, we explore the prevalence of this emerging class of peptides, which we have named Secreted, Cysteine-rich REpeat Peptides, or "SCREPs." To achieve this, we have employed data mining techniques to extract SCREP-like sequences from the UniProtKB database, yielding approximately sixty thousand candidates. These results indicate that SCREPs exist within a diverse range of species with greatly varying sizes and predicted fold types, and likely include peptides with novel structures and unique modes of action. We present our approach to mining this database for discovery of novel ion-channel modulators and discuss a number of "hits" as promising leads for further investigation. Our database of SCREPs thus constitutes a novel resource for biodiscovery and highlights the value of a data-driven approach to the identification of new bioactive pharmacological tools and therapeutic lead molecules.

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A novel group of multi-GAP-domain proteins.

Publications

A novel group of multi-GAP-domain proteins.

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