Splice-specific functions of gephyrin in molybdenum cofactor biosynthesis

The Journal of Biological Chemistry
Birthe SmolinskyGuenter Schwarz

Abstract

Gephyrin is a multifunctional protein involved in the clustering of inhibitory neuroreceptors. In addition, gephyrin catalyzes the last step in molybdenum cofactor (Moco) biosynthesis essential for the activities of Mo-dependent enzymes such as sulfite oxidase and xanthine oxidoreductase. Functional complexity and diversity of gephyrin is believed to be regulated by alternative splicing in a tissue-specific manner. Here, we investigated eight gephyrin variants with combinations of seven alternatively spliced exons located in the N-terminal G domain, the central domain, and the C-terminal E domain. Their activity in Moco synthesis was analyzed in vivo by reconstitution of gephyrin-deficient L929 cells, which were found to be defective in the G domain of gephyrin. Individual domain functions were assayed in addition and confirmed that variants containing either an additional C5 cassette or missing the C6 cassette are inactive in Moco synthesis. In contrast, different alterations within the central domain retained the Moco synthetic activity of gephyrin. The recombinant gephyrin G domain containing the C5 cassette forms dimers in solution, binds molybdopterin, but is unable to catalyze molybdopterin (MPT) adenylylation. Determinat...Continue Reading

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Citations

Aug 23, 2008·Histochemistry and Cell Biology·Thomas DresbachJoachim Kirsch
Jan 25, 2012·Histochemistry and Cell Biology·Ralph NawrotzkiJoachim Kirsch
May 31, 2011·Metallomics : Integrated Biometal Science·Angel LlamasAurora Galván
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