Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

Abstract

Fascin-1-mediated actin-bundling activity is central to the generation of plasma membrane protrusions required for cell migration. Dysregulated formation of cellular protrusions is observed in metastatic cancers, where they are required for increased invasiveness, and is often correlated with increased Fascin-1 abundance. Therefore, there is interest in generating therapeutic Fascin-1 inhibitors. We present the identification of Nb 3E11, a nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. The crystal structure of the Fascin-1/Nb 3E11 complex reveals the structural mechanism of inhibition. Nb 3E11 occludes an actin-binding site on the third β-trefoil domain of Fascin-1 that is currently not targeted by chemical inhibitors. Binding of Nb 3E11 to Fascin-1 induces a conformational change in the adjacent domains to stabilize Fascin-1 in an inhibitory state similar to that adopted in the presence of small-molecule inhibitors. Nb 3E11 could be used as a tool inhibitor molecule to aid in the development of Fascin-1 targeted therapeutics.

People
Burgess, Selena G.
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

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Paul, Nikki R.
Author
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Richards, Mark W.
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

See full publications list
Ault, James R.
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

See full publications list
Askenatzis, Laurie
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

See full publications list
Claydon, Sophie G.
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

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Corbyn, Ryan
Author

Xavier, Vanessa and Martinelli, Silvia and Corbyn, Ryan and Pennie, Rachel and Rakovic, Kai and Powley, Ian R. and Officer-Jones, Leah and Ruscica, Vincenzo and Galloway, Alison and Carlin, Leo M. and Cowling, Victoria H. and Le Quesne, John and Martinou, Jean-Claude and MacVicar, Thomas (2024) Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression. Life Science Alliance, 7 (11): e202402764. ISSN 2575-1077

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

See full publications list
Machesky, Laura M.
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

See full publications list
Bayliss, Richard
Author

Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard (2024) A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. Open Biology, 14 (3): 230376. ISSN 2046-2441

See full publications list
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Information
Title:
A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation
Creators:
Burgess, Selena G. and Paul, Nikki R. and Richards, Mark W. and Ault, James R. and Askenatzis, Laurie and Claydon, Sophie G. and Corbyn, Ryan and Machesky, Laura M. and Bayliss, Richard
Identification Number:
10.1098/rsob.230376
Date:
20 March 2024
Divisions:
College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
The Royal Society
Additional Information:
Funding. Cancer Research UK grant no. C24461/A23303 (R.B.), Cancer Research UK grant nos. A24452, A17196 and A31287 (L.M.M.), Pancreatic Cancer Research Fund (L.M.M.), Medical Research Council grant no. MR/R017255/1 (L.M.M.), EPSRC grant no. EP/T002123/1 (L.M.M.), Project Development Fund of Cancer Research UK, BBSRC grant no. BB/M012573/1 (Biomolecular Mass Spectrometry Facility, University of Leeds).
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URI:
https://pub.demo35.eprints-hosting.org/id/eprint/324
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
SWORD Depositor:
Users 37347 not found.
Date Deposited:
11 Jun 2025 16:37
Revision:
20
Last Modified:
12 Jun 2025 09:48
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