Structural and Mechanistic Insights into Ras Association Domains of Phospholipase C Epsilon

SummaryRas proteins signal to a number of distinct pathways by interacting with diverse effectors. Studies of ras/effector 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 (PLCɛ). We solved structures of PLCɛ RA domains (RA1 and RA2) by NMR and the structure of the RA2/ras complex by X-ray crystallography. Although the similarity between ubiquitin-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 PLCɛ, while the ability to make contacts with both switch I and II regions of ras is shared only with phosphatidylinositol-3-kinase. Studies of PLCɛ regulation suggest that, in a cellular context, the RA2 domain, in a mode specific to PLCɛ, has a role in membrane targeting with further regulatory impact on PLC activity.