Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements

<p><span><span><span><span><span><span><span><span><span><span><span>Phospholipase Cepsilon (PLCepsilon) generates lipid-derived second messengers in the cardiovascular system at the plasma and perinuclear membranes. It is activated in response to a wide variety of signals, such as those conveyed by Rap1A and Ras, through a mechanism that involves its C-terminal Ras association (RA) domains (RA1 and RA2). However, the complexity and size of PLCepsilon has hindered its structural and functional analysis. In this manuscript, we report the 2.7 Å crystal structure of fragment of PLCepsilon that retains catalytic activity. The strutcure includes the RA1 domain, which forms an integral part of the conserved core. In addition, a highly conserved amphipathic helix in the autoinhibitory X–Y linker is shown to modulate activity <em>in vitro</em> and in cells. </span></span></span></span></span></span></span></span></span></span></span><span><span><span><span><span><span><span><span><span><span><span>The studies provide a structural framework for  the core of this critical cardiovascular enzyme that will allow for a better understanding of its regulation and roles in disease.</span></span></span></span></span></span></span></span></span></span></span></p>