Strained actin binding by the Prickle2 LIM domains and their regulation in the full-length protein

Cells sense mechanical changes in their cytoskeletal network via force-sensing actin-binding proteins. Recently, a novel force-sensing mechanism was described whereby Lin11, Isl- 1, and Mec-3 (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) is associated with strained actin filaments in <i>Xenopus</i> 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 Prickle, Espinas, Testin (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.