Dynamics of ezrin and EBP50 in regulating microvilli on the apical aspect of epithelial cells

Abstract

Microvilli are found on the apical surface of epithelial cells. Recent studies on the microvillar proteins ezrin and EBP50 (ezrin/radixin/moesin-binding phosphoprotein of 50 kDa) have revealed both the dynamics and the regulation of microvillar components, and how a dynamic ezrin phosphocycle is necessary to confine microvilli to the apical membrane. In the present review, we first summarize the background to allow us to place these advances in context.

Figure 1. Sequential recruitment and dynamics of ezrin and EBP50 in microvilli

(1) Ezrin is recruited to microvilli in the dormant autoinhibited form by its affinity for membrane PtdIns(4,5) P₂ (pink). (2) PtdIns(4,5) P₂ binding induces a conformation change in ezrin partially transitioning it to the open state, which is stabilized further by threonine phosphorylation within the C-terminal domain by LOK/SLK. (3) Open ezrin then engages in interaction with the F-actin core through its C-terminal domain and the basic juxtamembrane region of an ERM-binding transmembrane protein through its N-terminal FERM domain. (4) Open ezrin also binds to EBP50 through its N-terminal FERM domain. Binding to ezrin reverses an autoinhibitory interaction between the EBP50 tail and its second PDZ domain. EBP50 is then free to bind PDZ ligands, but, interestingly, instead of forming a stable complex, PDZ ligand binding promotes exchange of ezrin-bound EBP50 with the unbound form (teal arrow) (5) As ezrin treadmills towards the microvillus base, it is dephosphorylated by the PP1 (protein phosphatase 1) complex. (6) Dephosphorylated ezrin and inactive EPB50 recycle into the cytoplasm. (7) The cycle repeats. Note that the ezrin phosphocycle and membrane occupancy cycle rates are lower than the rate of EBP50 exchange between the cytoplasm and microvillar membrane.