What is it about?
How cells specify morphologically distinct plasma membrane domains is poorly understood. Prior work has shown that restriction of microvilli to the apical aspect of epithelial cells requires the localized activation of the membrane-F-actin linking protein ezrin. Using an in vitro system, we now define a multi-step process whereby the kinase LOK specifically phosphorylates ezrin to activate it. Binding of PIP2 to ezrin induces a conformational change permitting the insertion of the LOK C-terminal domain to wedge apart the membrane and F-actin-binding domains of ezrin. The N-terminal LOK kinase domain can then access a site 40 residues distal from the consensus sequence that collectively direct phosphorylation of the appropriate threonine residue. We suggest that this elaborate mechanism ensures that ezrin is only phosphorylated at the plasma membrane, and with high specificity by the apically localized kinase LOK.
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Why is it important?
Phosphorylation of ezrin involves an unusual mechanism requiring coincident binding to PIP2 and involvement of the non-catalytic domain to gain access to the phosphorylation site thereby restricting selective phosphorylation to the plasma membrane.
Perspectives
While substrate specificity of protein kinases has been the subject of many studies (Ubersax and Ferrell, 2007), fewer cases of conditional specificity have been examined in detail, with LOK-mediated ezrin phosphorylation being the first example of a specific requirement for a phosphoinositide binding to the substrate. As complex cell behaviors rely on the proper timing of phosphorylation events, such intimate co-regulation between substrates and kinases as described in our paper may emerge as a general theme.
Dr Thaher Pelaseyed
Cornell University Department of Biological and Environmental Engineering
Read the Original
This page is a summary of: Ezrin activation by LOK phosphorylation involves a PIP2-dependent wedge mechanism, eLife, April 2017, eLife,
DOI: 10.7554/elife.22759.
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