Stressed Actin Binding by the Prickle2 LIM Domains and its Regulation in the Full-Length Protein.

Cells are capable of sensing mechanical changes in their cytoskeletal network via stress-sensitive actin-binding proteins. Recently, a novel stress-sensing mechanism was described whereby LIM domains from diverse protein families bind directly to stressed 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 stressed actin filaments in mesoderm alongside known stress-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 stressed actin and promote recruitment to Pk2-rich nodes. 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 stress-sensitive LIM domains and may inform our understanding of planar cell polarity.