A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation

被引：1
|
作者：
Burgess, Selena G. [1 ]
Paul, Nikki R. [2 ]
Richards, Mark W. [1 ]
Ault, James R. [1 ]
Askenatzis, Laurie [2 ]
Claydon, Sophie G. [2 ,3 ]
Corbyn, Ryan [2 ]
Machesky, Laura M. [2 ,3 ,4 ]
Bayliss, Richard [1 ]
机构：
[1] Univ Leeds, Fac Biol Sci, Astbury Ctr Struct Mol Biol, Sch Mol & Cellular Biol, Leeds LS2 9JT, England
[2] Canc Res UK Beatson Inst, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Scotland
[3] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Scotland
[4] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England
来源：
OPEN BIOLOGY | 2024年 / 14卷 / 03期
基金：
英国生物技术与生命科学研究理事会;
关键词：
nanobody; Fascin-1; actin; cell migration; actin-bundling inhibitor; F-ACTIN; STRUCTURAL BASIS; CROSS-LINKING; BINDING; DOMAIN; EXPRESSION; ANTIBODIES; IDENTIFICATION; MECHANISM; CORTACTIN;
D O I：
10.1098/rsob.230376
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 beta-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.
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页数：15
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