The LOK C-terminus is an IBAR-like domain that facilitates membrane binding and ezrin colocalization.

The lymphocyte-oriented kinase (LOK, also known as STK10) is a critical regulator of membrane tension and an important oncogenic target that mediates the epithelial-to-mesenchymal transition. LOK regulates membrane dynamics through phosphorylation of ezrin/radixin/moesin domain proteins, but the molecular mechanisms through which LOK is able to target to its substrate are yet unknown. Here, we show that LOK and ezrin colocalize at the apical surface of epithelial cells via the LOK C-terminal domain (LOK-CTD). We demonstrate that the LOK-CTD mediates the formation of LOK dimers as well as binding to negatively charged phospholipids and shares structural similarities to inverse Bin/amphiphysin/Rvs domains via a combination of biochemical assays and predictive bioinformatics. We confirm the stability of the LOK-CTD inverse Bin/amphiphysin/Rvs-like dimer via atomistic and coarse-grained molecular dynamics simulations and human cell-based assays to demonstrate the functional significance of the LOK-CTD in mediating colocalization with the FERM domain of ezrin.