Structural and mechanistic insights into ras association domains of phospholipase C epsilon

Ras proteins signal to a number of distinct pathways by interacting with diverse effectors. Studies of ras/effect or interactions have focused on three classes, Raf kinases, ral guanylnucleotide-exchange factors, and phosphatidylinositol-3-kinases. Here we describe ras interactions with another effector, the recently identified phospholipase C epsilon (PLC epsilon). We solved structures of PLC epsilon RA domains (RA1 and RA2) by NMR and the structure of the RA2/ras complex by X-ray crystallography. Although the similarity between ubiqultin-like folds of RA1 and RA2 proves that they are homologs, only RA2 can bind ras. Some of the features of the RA2/ras interface are unique to PLC epsilon, while the ability to make contacts with both switch I and II regions of ras is shared only with phosphatidylinositol-3-kinase. Studies of PLC epsilon regulation suggest that, in a cellular context, the RA2 domain, in a mode specific to PLC epsilon, has a role in membrane targeting with further regulatory impact on PLC activity.