VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse.
EMBO J
; 27(24): 3221-34, 2008 Dec 17.
Article
en En
| MEDLINE
| ID: mdl-19037259
ABSTRACT
The signalling lipid PI(3,5)P(2) is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P(2) levels. Mutations that lower PI(3,5)P(2) cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P(2) 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)P(2) regulatory complex by direct contact with the known regulators of PI(3,5)P(2) 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)P(2) regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P(2). Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fosfatidilinositoles
/
Saccharomyces cerevisiae
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Fosfatos de Fosfatidilinositol
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Péptidos y Proteínas de Señalización Intracelular
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Proteínas de la Membrana
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Ratones
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
EMBO J
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos