3P53

Structure of fascin

3P53 の概要

• エントリーDOI: 10.2210/pdb3p53/pdb
• 分子名称: Fascin, GLYCEROL, DODECAETHYLENE GLYCOL, ... (6 entities in total)
• 機能のキーワード: beta-trefoil domain, structural protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton: Q16658
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112331.24

構造登録者

Jansen, S.,Dominguez, R. (登録日: 2010-10-07, 公開日: 2011-06-29, 最終更新日: 2024-02-21)

主引用文献

Jansen, S.,Collins, A.,Yang, C.,Rebowski, G.,Svitkina, T.,Dominguez, R.
Mechanism of actin filament bundling by fascin.
J.Biol.Chem., 286:30087-30096, 2011

PubMed Abstract: 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 β-trefoil domains. Here, we show that fascin contains two major actin-binding sites, coinciding with regions of high sequence conservation in β-trefoil domains 1 and 3. The site in β-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 β-trefoil-3 is related by pseudo-2-fold symmetry to that in β-trefoil-1. The two sites are ∼5 nm apart, resulting in a distance between actin filaments in the bundle of ∼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.

PubMed: 21685497
DOI: 10.1074/jbc.M111.251439

実験手法

X-RAY DIFFRACTION (2 Å)