Mol Biol Cell 2025 Oct 29;:mbcE25050244. doi: 10.1091/mbc.E25-05-0244.

Strained Actin Binding by the Prickle2 LIM Domains and their Regulation in the Full-Length Protein.

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Cells sense mechanical changes in their cytoskeletal network via force-sensing actin-binding proteins. Recently, a novel force-sensing mechanism was described whereby LIM domains from diverse protein families bind directly to strained actin filaments. It remains unclear, however, how the interaction of these domains with actin is regulated in the context of full-length proteins. Here, we show that the LIM domain containing region (LCR) of the planar cell polarity protein Prickle2 (Pk2) associated with strained actin filaments in Xenopus mesoderm alongside known strain-sensitive LIM domains. By contrast, the full-length Pk2 did not exhibit similar recruitment along actin filaments. Structure function analysis revealed that both the structured PET domain and unstructured C-terminal region of Pk2 suppress recruitment of Pk2's LCR to strained actin and promote recruitment to Pk2-rich nodes. Notably, fusion of Pk2's PET domain with the LIM domains of the cytoskeletal proteins Testin and Zyxin revealed context-dependence of this inhibitory effect. Finally, we show that two human patient-derived variants associated with epilepsy result in a loss of Pk2-LCR recruitment to actin filaments. These data provide new insights into the regulation of strain-sensitive LIM domains and may inform our understanding of planar cell polarity.

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