VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast and mouse
| Autor: | Sujin Park, Yanling Zhang, Dan Goldowitz, Li Liu, Natsuko Jin, Muriel T. Davisson, Miriam H. Meisler, Clement Y. Chow, Roderick T. Bronson, Jason E. Duex, Jason L. Petersen, Lois S. Weisman, Sergey N. Zolov |
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| Rok vydání: | 2008 |
| Předmět: |
0303 health sciences
Mutation Phosphatidylinositol 3 5-bisphosphate General Immunology and Microbiology biology Endosome General Neuroscience Saccharomyces cerevisiae Mutant Plasma protein binding medicine.disease_cause biology.organism_classification General Biochemistry Genetics and Molecular Biology 03 medical and health sciences PIKFYVE chemistry.chemical_compound 0302 clinical medicine Biochemistry chemistry Pi medicine Molecular Biology 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | The EMBO Journal. 27:3221-3234 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.1038/emboj.2008.248 |
| Popis: | The signalling lipid PI(3,5)P2 is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P2 levels. Mutations that lower PI(3,5)P2 cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P2 was uncharacterized previously. Here, we predict that yeast and mammalian Vac14 are composed entirely of HEAT repeats and demonstrate that Vac14 exerts an effect as a scaffold for the PI(3,5)P2 regulatory complex by direct contact with the known regulators of PI(3,5)P2: Fig4, Fab1, Vac7 and Atg18. We also report that the mouse mutant ingls (infantile gliosis) results from a missense mutation in Vac14 that prevents the association of Vac14 with Fab1, generating a partial complex. Analysis of ingls and two additional mutants provides insight into the organization of the PI(3,5)P2 regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P2. Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse. |
| Databáze: | OpenAIRE |
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