Editors' ChoiceProtein Motifs

PI3P Attracts PX Domains

See allHide authors and affiliations

Science's STKE  10 Jul 2001:
Vol. 2001, Issue 90, pp. tw2
DOI: 10.1126/stke.2001.90.tw2

Four papers this week (Kanai et al., Ellson et al., Cheever et al., and Xu et al.) show that the PX (phox homology) domain binds to inositol lipids phosphorylated on the 3 position [(phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol-3,4-bisphophate (PI3,4P2)], the products of phosphatidylinositol 3-kinase (PI3K). In neutrophils and other phagocytic cells, two subunits of NADPH oxidase (p40phox and p47phox) are kept in the cytosol until cells are activated. Upon activation, which involves activation of PI3K, these two subunits are recruited to secretory vesicles and granules where the remaining subunits are located. These vesicles then fuse with the plasma membrane and phagosomes leading to production of reactive oxygen species (ROS). Kanai et al. show that p40phox binds preferentially to PI3P and p47phox binds preferentially to PI3,4P2 and that binding to the endosomal membranes depends on PI3P production and an intact PX domain. Ellson et al. used ROS assays to determine that PI3P was essential for activation of ROS. Furthermore, the component binding PI3P was identified as p40phox by surface plasmon resonance assays, and the PX domain was sufficient to target a reporter protein to endosomes. The identification of this phospholipid-binding motif provides an essential missing piece in the puzzle of why PI3K is important for regulating neutrophil function and inflammatory processes. The remaining two papers address this motif in proteins involved in targeting proteins to the vacuole in yeast (Cheever et al.) and in sorting proteins in the endosomal system (Xu et al.). Thus, the PX domain is a common motif that allows protein trafficking to be controlled by the activity of PI3K and the production of PI3P species.

F. Kanai, H. Liu, S. J. Field, H. Akbary, T. Matsuo, G. E. Brown, L. C. Cantley, M. B. Yaffe, The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nature Cell Biol. 3, 675-678 (2001). [Online Journal]

C. D. Ellson, S. Gobert-Gosse, K. E. Anderson, K. Davidson, H. Erdjument-Bromage, P. Tempst, J. W. Thuring, M. A. Cooper, Z.-Y. Lim, A. B. Holmes, P. T. J. Gaffney, J. Coadwell, E. R. Chilvers, P. T. Hawkins, L. R. Stephins, PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40phox. Nature Cell Biol. 3, 679-682 (2001). [Online Journal]

M. L. Cheever, T. K Sato, T. de Beer, T. G. Kutateladze, S. D. Emr, M. Overduin, Phox domain interaction with PdtIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nature Cell Biol. 3, 613-618 (2001). [Online Journal]

Y. Xu, H. Hortsman, L. Seet, S. H. Wong, W. Hong, SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nature Cell Biol. 3, 658-666 (2001). [Online Journal]

Stay Connected to Science Signaling