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PX domain

Class: Phospholipid Binding

Brief description: The PX domain is a structural module composed of 100 to 140 amino acids that was first identified in the p40phox and p47phox subunits of NADPH oxidas. Since then, more than 100 PX domain-containing proteins have been identified in eukaryotes from yeast to humans. In general, conservation between PX domains is relatively low. Many PX domain proteins function in a variety of distinct biological processes that involve specific membrane compartments. Some PX domains are involved in the docking and fusion of transport vesicles to the lysosome-like vacuole in yeast. The PX domains from Vam7, p40phox, and SNX3 specifically bind PtdIns(3)P and targets them to their sites of function. However, not all PX domains bind PtdIns(3)P. The PX domain of p47phox preferentially binds to PtdIns(3,4)P2, whereas the human class II PI3K C2- PX domain binds PtdIns(4,5)P2. So different PX domains possess preferences for different PIs, likely reflecting the variability within the PX domain sequence.

Structure:

structure The crystal structure of the p40phox-PtdIns(3)P complex illustrated two lobes between whom lies the binding cleft. The crystal structure of CISK-PX showed that this domain also has all the basic residues necessary for binding the 3-phosphate of PtdIns(3)P. The X-ray structure of the PX domain of p47phox revealed that this PX domain has two phospholipid-binding sites for PtdIns(3,4)P2, respectively, and PA (or PS), respectively. For some cases, lipid-induced local conformational changes involving putative membrane-penetrating hydrophobic residues were also shown. Penetration of the PX domain into the membrane may orient two basic motifs toward the inositol phosphates.

Subcellular Localization:

Many PX domains that bind PtdIns(3)P-binding , including the p40phox PX domain, are localized at early endosomes upon ectopical expression. Many yeast proteins containing low-affinity PX domains have been found in multiprotein complexes. The GFP-tagged p47 phox PX was also found in the cytosol in HEK293 cells. However, upon feeding cells with PtdIns(3,4)P2, the p47phox PX selectively localized to the PS-rich plasma membranes.

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Relevant Literature

1. Hiroaki, H., Ago, T., Ito, T., Sumimoto, H. and Kohda, D. (2001) Solution structure of the PX domain, a target of the SH3 domain. Nat Struct Biol, 8, 526-530.

2. Ellson, C.D., Andrews, S., Stephens, L.R. and Hawkins, P.T. (2002) The PX domain: a new phosphoinositide-binding module. J Cell Sci, 115, 1099-1105.

3. Ellson, C.D., Gobert-Gosse, S., Anderson, K.E., Davidson, K., Erdjument-Bromage, H., Tempst, P., Thuring, J.W., Cooper, M.A., Lim, Z.Y., Holmes, A.B. et al. (2001) PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox). Nat Cell Biol, 3, 679-682.

4. Xing, Y., Liu, D., Zhang, R., Joachimiak, A., Songyang, Z. and Xu, W. (2004) Structural basis of membrane targeting by the phox homology domain of cytokine-independent survival kinase (CISK-PX). J Biol Chem.

5. Stahelin, R.V., Burian, A., Bruzik, K.S., Murray, D. and Cho, W. (2003) Membrane binding mechanisms of the PX domains of NADPH oxidase p40phox and p47phox. J Biol Chem, 278, 14469-14479.