3p53

Structure of fascin

spinqualitylabelsall models 3p53, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3p53 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 12P, 1PE, GOL, PG0 Gene: FAN1, FSCN1, HSN, Human, SNL (HUMAN) Resources: FirstGlance, OCA, RCSB, PDBsum Function [FSCN1_HUMAN] Organizes filamentous actin into bundles with a minimum of 4.1:1 actin/fascin ratio. Plays a role in the organization of actin filament bundles and the formation of microspikes, membrane ruffles, and stress fibers. Important for the formation of a diverse set of cell protrusions, such as filopodia, and for cell motility and migration. Publication Abstract from PubMed Fascin is the main actin filament bundling protein in filopodia. Because of the important role filopodia play in cell migration, fascin is emerging as a major target for cancer drug discovery. However, an understanding of the mechanism of bundle formation by fascin is critically lacking. Fascin consists of four beta-trefoil domains. Here, we show that fascin contains two major actin-binding sites, coinciding with regions of high sequence conservation in beta-trefoil domains 1 and 3. The site in beta-trefoil-1 is located near the binding site of the fascin inhibitor macroketone and comprises residue Ser-39, whose phosphorylation by protein kinase C down-regulates actin bundling and formation of filopodia. The site in beta-trefoil-3 is related by pseudo-2-fold symmetry to that in beta-trefoil-1. The two sites are approximately 5 nm apart, resulting in a distance between actin filaments in the bundle of approximately 8.1 nm. Residue mutations in both sites disrupt bundle formation in vitro as assessed by co-sedimentation with actin and electron microscopy and severely impair formation of filopodia in cells as determined by rescue experiments in fascin-depleted cells. Mutations of other areas of the fascin surface also affect actin bundling and formation of filopodia albeit to a lesser extent, suggesting that, in addition to the two major actin-binding sites, fascin makes secondary contacts with other filaments in the bundle. In a high resolution crystal structure of fascin, molecules of glycerol and polyethylene glycol are bound in pockets located within the two major actin-binding sites. These molecules could guide the rational design of new anticancer fascin inhibitors. Mechanism of actin filament bundling by fascin.,Jansen S, Collins A, Yang C, Rebowski G, Svitkina T, Dominguez R J Biol Chem. 2011 Aug 26;286(34):30087-96. Epub 2011 Jun 18. PMID:21685497 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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