Molecular Mechanism of Fascin Function in Filopodial Formation

Yang, Shengyu; Huang, Fang Ke; Huang, Jian; Chen, Shuai; Jakoncic, Jean; Leo‐Macias, Alejandra; Díaz-Avalos, Rubén; Chen, Lin; Zhang, J. Jillian; Huang, Xin

doi:10.1074/jbc.m112.427971

Cited by 109 publications

(185 citation statements)

References 45 publications

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“…The rationales were: (i) It is the actinbundling activity of fascin that is important for tumour cell migration and invasion. (ii) Based on the X-ray crystal structure of fascin, there are many potential binding sites on fascin for small molecules, in addition to the two main actin-binding pockets 44 . Some fascin-binding compounds might not inhibit the actin-bundling function of fascin.…”

Section: Resultsmentioning

confidence: 99%

“…1). This method was an adaptation of a method that we used previously 35,44 . Because the F-actin filaments or F-actin bundles bear negative charges, we reasoned that a positively charged surface would be able to capture the F-actin filaments and bundles (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We used cryo-electron tomography and analysed the in vitro reconstituted unconstrained three-dimensional (3D) bundles formed by fascin and actin filaments. These bundles consisted of a hexagonal lattice of parallel actin filaments where fascin formed the crossbridges, and these bundles were similar to the filopodial bundles isolated from native tissues/cells 44 .…”

mentioning

confidence: 76%

“…Previously, we solved the X-ray crystal structures of the wildtype fascin and four fascin mutants to define the active and inactive configurations of fascin, and revealed the structural basis for the conformational changes of fascin during the actin-binding process 35,44 . From a systematic mutagenesis study of 100 fascin mutants, we identified at least two major actin-binding sites on fascin, and that each of these actin-binding sites is essential for the filopodial formation in cells 44 .…”

mentioning

confidence: 99%

“…From a systematic mutagenesis study of 100 fascin mutants, we identified at least two major actin-binding sites on fascin, and that each of these actin-binding sites is essential for the filopodial formation in cells 44 . We used cryo-electron tomography and analysed the in vitro reconstituted unconstrained three-dimensional (3D) bundles formed by fascin and actin filaments.…”

mentioning

confidence: 99%

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Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

et al. 2015

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One of the key steps during tumour metastasis is tumour cell migration and invasion, which require actin cytoskeletal reorganization. Among the critical actin cytoskeletal protrusion structures are the filopodia, which act like cell sensory organs to communicate with the extracellular microenvironment and participate in fundamental cell functions such as cell adhesion, spreading and migration in the three-dimensional environment. Fascin is the main actin-bundling protein in filopodia. Using high-throughput screening, here we identify and characterize small molecules that inhibit the actin-bundling activity of fascin. Focusing on one such inhibitor, we demonstrate that it specifically blocks filopodial formation, tumour cell migration and invasion in vitro, and metastasis in vivo. Hence, target-specific anti-fascin agents have a therapeutic potential for cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 76%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

et al. 2015

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Crowding tunes the organization and mechanics of actin bundles formed by crosslinking proteins

Park

Lee

et al. 2020

FEBS Letters

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Fascin and α‐actinin form higher‐ordered actin bundles that mediate numerous cellular processes including cell morphogenesis and movement. While it is understood crosslinked bundle formation occurs in crowded cytoplasm, how crowding affects the bundling activities of the two crosslinking proteins is not known. Here, we demonstrate how solution crowding modulates the organization and mechanical properties of fascin‐ and α‐actinin‐induced bundles, utilizing total internal reflection fluorescence and atomic force microscopy imaging. Molecular dynamics simulations support the inference that crowding reduces binding interaction between actin filaments and fascin or the calponin homology 1 domain of α‐actinin evidenced by interaction energy and hydrogen bonding analysis. Based on our findings, we suggest a mechanism of crosslinked actin bundle assembly and mechanics in crowded intracellular environments.

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Prediction of The Binding Mode of NP‐G2‐044 Targeting Fascin and Its Drug Resistance Mutations

Pan,

Wang,

et al. 2023

Advcd Theory and Sims

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Fascin is a major actin‐binding protein (ABP) in filopodia and is highly expressed in metastatic tumors. To inhibit its function, a potent inhibitor called NP‐G2‐044 is currently in phase II clinical trials. However, the binding mode of this inhibitor remains unclear. In this study, the binding mode of NP‐G2‐044 in fascin and predicted drug resistance mutations is investigated. The rough binding position and pose can be deduce based on information from its derivant NP‐G2‐029, whose crystal structure with fascin has been solved. Molecular docking, free energy perturbation (FEP) simulation and metadynamics simulation are performed to confirm the binding pose. Based on the molecular docking results, two binding modes of NP‐G2‐044, pose A and B, are obtained, with pose A being more favorable. For pose A, the planar indazole moiety has the same orientation as NP‐G2‐029 in the complex with fascin, while for pose B, it rotates ≈90°. FEP and metadynamics simulations indicate that both binding poses are possible. Relative binding free energies for mutation effects calculated by FEP predict E215A and R217A are drug resistance mutations. These findings are important for further drug development targeting fascin.

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Molecular Mechanism of Fascin Function in Filopodial Formation

Cited by 109 publications

References 45 publications

Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

Crowding tunes the organization and mechanics of actin bundles formed by crosslinking proteins

Prediction of The Binding Mode of NP‐G2‐044 Targeting Fascin and Its Drug Resistance Mutations

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