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The PX domain: a new phosphoinositide-binding module

¹ The Inositide Laboratory, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK
² Bioinformatics, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

View larger version (41K): [in a new window]   Fig. 1. Domain profiles of all PX-domain-containing proteins. Proteins were selected from the SMART database (Schultz et al., 2000), aligned, and unique proteins are shown (proteins with >80% homology were excluded as redundant or orthologous). Where appropriate, the human version is shown. Species abbreviations precede the accession numbers; At, A. thaliana; Ca, C. albicans; Ce, C.elegans; Dm, D. melanogaster; Hs, H.sapiens; Mm, M.musculus; Nc, N.crassa; Os. O.satvia; Sc, S.cerevisiae; Sp, S.pombe; Tb, T.brucei brucei; Um, U.maydis. The residue at the at the equivalent position to Arg58 of p40phox is shown as the standard single letter amino acid code in each PX domain. Domains with a basic residue (R or K) at this position are suggested to bind 3-phosphoinositides, whereas domains lacking a basic residue are predicted to bind other phosphoinositide species (see text).

View larger version (35K): [in a new window]   Fig. 2. (A) Secondary structure of the p40phox PX domain. The first -helix is not part of the core PX domain but was included in the crystallised p40phox PX domain construct. MIL, membrane interaction loop; PxxP, polyproline region. (B) Tertiary structure of the overall topology of the p40phox PX domain bound to PtdIns(3)P. The membrane interaction loop of the PX domain and the acyl chains of the PtdIns(3)P would insert into a membrane located towards the top of the diagram. (C) Details of the lipid-binding pocket shown in (B). Key residues are illustrated to demonstrate how each one is positioned to fulfil specific roles; Lys92 hydrogen bonds with the 1-phosphate, Tyr59 stacks against the inositol ring, Arg105 interacts with the 4- and 5-hydroyl groups, Arg58 contacts the 3-phosphate and Arg57 faces away from the lipid binding pocket, fulfilling a structural role in the domain.

View larger version (39K): [in a new window]   Fig. 3. (A) A model for the role of Vam7p in vesicle-vacuole docking. Vam7p is localised to the vacuole by interaction of its PX domain with PtdIns(3)P and through interaction with Vam3 (explaining how overexpression of Vam7pPX can still facilitate docking, as it can be localised through Vam3, albeit to a lower extent than the wild type). The cargo vesicle docks to Vam7p through Vti1, and the Class C Vps complex also joins. Assembly of this complex facilitates vesicle-vacuole fusion (Sato et al., 2000). (B) A model of regulation of CISK by interaction with phosphoinositides. CISK is localised to membranes by PtdIns(3)P or PtdIns(3,4,5)P3. This may allow it to be activated through phosphorylation by an upstream kinase, perhaps PDK or a PDK-like kinase. Once active, CISK can phosphorylate downstream targets to exert effects on cell survival.

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