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Title

Type I phosphatidylinositol 4-phosphate 5-kinase homo- and heterodimerization determines its membrane localization and activity

AuthorsLacalle, Rosa Ana; Karam, Juan C. de; Martínez Muñoz, Laura; Artetxe, Ibai; Peregil, Rosa M.; Sot, Jesús; Rojas, A. M. ; Goñi, Félix M.; Mellado, Mario; Mañes, Santos
KeywordsPIP5K
Dimerization
Lipid kinase
PI(4,5)P2
Issue DateJun-2015
PublisherFederation of American Societies for Experimental Biology
CitationFASEB Journal 29(6): 2371-2385 (2015)
AbstractType I phosphatidylinositol 4-phosphate 5-kinases (PIP5KIs; α, β, and γ) are a family of isoenzymes that produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] using phosphatidylinositol 4-phosphate as substrate. Their structural homology with the class II lipid kinases [type II phosphatidylinositol 5-phosphate 4-kinase (PIP4KII)] suggests that PIP5KI dimerizes, although this has not been formally demonstrated. Neither the hypothetical structural dimerization determinants nor the functional consequences of dimerization have been studied. Here, we used Förster resonance energy transfer, coprecipitation, and ELISA to show that PIP5KIβ forms homo- and heterodimers with PIP5KIγ_i2 in vitro and in live human cells. Dimerization appears to be a general phenomenon for PIP5KI isoenzymes because PIP5KIβ/PIP5KIα heterodimers were also detected by mass spectrometry. Dimerization was independent of actin cytoskeleton remodeling and was also observed using purified proteins. Mutagenesis studies of PIP5KIβ located the dimerization motif at the N terminus, in a region homologous to that implicated in PIP4KII dimerization. PIP5KIβ mutants whose dimerization was impaired showed a severe decrease in PI(4,5)P2 production and plasma membrane delocalization, although their association to lipid monolayers was unaltered. Our results identify dimerization as an integral feature of PIP5K proteins and a central determinant of their enzyme activity.—Lacalle, R. A., de Karam, J. C., Martínez-Muñoz, L., Artetxe, I., Peregil, R. M., Sot, J., Rojas, A. M., Goñi, F. M., Mellado, M., Mañes, S. Type I phosphatidylinositol 4-phosphate 5-kinase homo- and heterodimerization determines its membrane localization and activity.
Publisher version (URL)http://doi.org/10.1096/fj.14-264606
URIhttp://hdl.handle.net/10261/153513
DOI10.1096/fj.14-264606
ISSN0892-6638
E-ISSN1530-6860
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