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First published online December 17, 2008
doi: 10.1242/10.1242/jcs.037135

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SNX9 – a prelude to vesicle release

Department of Medical Biochemistry and Biophysics, Umeå University, S-90187 Umeå, Sweden

View larger version (14K): [in this window] [in a new window]   Fig. 1. Vesicular and tubular endocytic pathways in the cell. The main uptake pathways involve clathrin-mediated endocytosis (CME), caveolae and clathrin-independent carriers/GPI-enriched endocytic compartments (CLIC/GEEC). Proteins that are involved in carrier formation and/or release are indicated below each pathway. Question marks indicate uncertainties or yet-to-be-established findings. GRAF1 is a recently described BAR-domain protein that marks, and is indispensable for, the CLIC/GEEC pathway (Lundmark et al., 2008).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Domain structure and interaction partners of SNX9. The domains are shown as colored rectangles, and numbers refer to the last amino acid in each domain in human SNX9. The sequences that form the yoke domain, which connects the PX and BAR domains in the tertiary structure, are from two regions that are denoted as YN and YC. The protein and phospholipid partners of SNX9 that are discussed in the text are shown. Further protein interaction partners that have been described in the literature, but are not shown in the figure, are as follows: ADAM9 and ADAM15 (Howard et al., 1999), Sos1 and Sos2 (Schulze and Mann, 2004), synaptojanin (Miele et al., 2004), phosphoinositide 3-kinase p85 (Badour et al., 2007) and PtdIns(4)P 5-kinase (Shin et al., 2008). Drosophila SNX9 has been reported to bind to WASP, AP-2, Dscam and Nck (Worby et al., 2001; Worby et al., 2002). Also indicated in the figure are two properties of the membrane-binding yoke-PX-BAR structural unit (membrane insertion and homodimerization).

View larger version (101K): [in this window] [in a new window]   Fig. 3. Structure of SNX9. (A) Ribbon diagram of the crystal structure of the membrane-remodeling yoke-PX-BAR dimer [Protein Data Bank (PDB) entry 2RAK], color-coded as in Fig. 2. In the upper structure, the membrane-binding surface is towards the viewer; the lower structure is a side view. Phosphoinositides (green) are bound to the canonical phosphoinositide-binding pockets. (B) Size comparison of SNX9 and dynamin. To the left is the full-length dimer of SNX9 with the electrostatic surface potential shown in red (negative charge) and blue (positive charge). The SH3-domain structure is from the PDB entry 2ENM and the LC domain is randomly depicted to denote its flexibility. To the right is a schematic model of dimeric dynamin that is drawn roughly to scale with SNX9. The model is based on cryoelectron micrographs (Mears et al., 2007). The GTPase domains of dynamin are the large balls at the top of the structure and the membrane-binding PH domains are at the bottom. The proline-rich domains (PRDs) are depicted as unstructured ribbons that emanate from the central region, which comprises the middle domains and the GTPase effector domains. The figure shows that the SNX9 SH3 domain and the dynamin PRD can interact with each other above the bulk of either protein and that SNX9 can reach out above dynamin to enable additional interactions, such as with N-WASP, while it is assembled on the membrane surface.

View larger version (56K): [in this window] [in a new window]   Fig. 4. Overexpression of the yoke-PX-BAR unit of SNX9 in cells produces numerous long membrane tubules. HeLa cells were transfected with a plasmid encoding Myc-tagged yoke-PX-BAR, stained with anti-Myc antibodies and fluorescently labeled secondary antibodies, and visualized by epifluorescence microscopy. Scale bar: 10 µm.

View larger version (24K): [in this window] [in a new window]   Fig. 5. Integration of SNX9 and dynamin function with actin remodeling during vesicular release. The figure shows a model that is outlined in the text. SNX9 recruits dynamin to the neck of a highly invaginated clathrin-coated pit. Ordered assembly of the proteins on the membrane surface leads to the formation of a narrow tubule that, through SNX9-assisted GTP hydrolysis by dynamin, becomes destabilized. Recruitment and activation of N-WASP by SNX9 triggers a burst of actin polymerization, which might aid in the final release of the vesicle.

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