RhoA allosterically activates phospholipase Cepsilon via its EF hands

<p><span style="font-size:medium"><span style="font-family:Aptos, sans-serif"><span style="color:#000000"><span style="font-style:normal"><span style="font-weight:400"><span style="white-space:normal"><span style="text-decoration:none"><span style="line-height:32px"><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black">Phospholipase C</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black"> (PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black">) cleaves phosphatidylinositol lipids to increase intracellular Ca<sup>2+</sup> and activate protein kinase C (PKC) in response to stimulation of cell surface receptors. PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black"> is activated via direct binding of small GTPases at the cytoplasmic leaflets of cellular membranes. In the cardiovascular system, the RhoA GTPase regulates PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black"> to initiate a pathway that protects against ischemia/reperfusion injuries, but the underlying molecular mechanism is not known. We present here the cryo-electron microscopy (cryo-EM) reconstruction of RhoA bound to PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black">, showing that the G protein binds a unique insertion within the PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black"> EF hands. Deletion of or mutations to this PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black"> insertion decrease RhoA-dependent activation without impacting regulation by other G proteins. Together, our data support a model wherein RhoA binding to PLC</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Symbol"><span style="color:black">e</span></span></span></span><span style="font-size:11pt"><span style="line-height:29.333336px"><span style="font-family:Arial, sans-serif"><span style="color:black"> allosterically activates the lipase and increases its interactions with the membrane, resulting in maximum activity and cardiomyocyte survival. </span></span></span></span></span></span></span></span></span></span></span></span></p>