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bioRxiv · 10.1101/2025.06.24.661301

Homodimerized Arpins: Binding to Arp2/3 Complexes with Positive Synergy to Inhibit Lamellipodia-Dependent Tumor Metastasis

Ye, S.·Liu, L.·Zhang, X.·Zhu, Y.·Pu, M.·Geng, Y.·Wang, M.·Zhang, R.·Ge, S.
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Abstract

The Arp2/3 complex is a central regulator of actin polymerization dynamics and cancer cell motility, with its dysregulation implicated in metastasis and therapeutic resistance. Despite its therapeutic potential, targeting Arp2/3 remains challenging due to the lack of precise molecular insights into endogenous inhibitors. Arpin, a lamellipodia-localized Arp2/3 inhibitor, has emerged as a critical modulator of cancer migration; however, the structural and mechanistic basis of its inhibitory function remains unresolved. Here, we report the 1.65-[A] crystal structure of Arpins N-terminal globular domain, revealing a unique structural fold distinct from all known Arp2/3-binding factors. Structural and biophysical analyses demonstrate that Arpin forms homodimers via a conserved interface, which is essential for cooperative inhibition of Arp2/3-dependent actin polymerization. Functional studies in cancer models reveal that Arpin homodimerization potently suppresses lamellipodia-driven migration and invasion, effects further enhanced by engineered dimeric constructs or artificially designed dual-tailed peptides. These findings elucidate a structural basis for Arpin-mediated suppression of cancer cell motility and identify homodimeric cooperativity as a druggable mechanism for targeting metastatic progression. Our work provides a molecular framework for designing Arpin-inspired inhibitors to counteract therapeutic resistance and metastasis in cancers reliant on Arp2/3-driven actin dynamics.

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Ye, S., Liu, L., Zhang, X., Zhu, Y., Pu, M., Geng, Y., Wang, M., Zhang, R., Ge, S.. 2025-06-24. Homodimerized Arpins: Binding to Arp2/3 Complexes with Positive Synergy to Inhibit Lamellipodia-Dependent Tumor Metastasis. https://doi.org/10.1101/2025.06.24.661301

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