616 Two years after the first description of the Pleckstrin homology (PH) domain [ 1,2] the recently published three-dimensional structures confirm the power of secondary structure predictions [ 31. Although the sequence similaritylidentity is low between different PH domains, a comparison of the structures indicates that they form highly similar protein modules analogous to the SH2 and SH3 domains [4-91. Despite the fact that PH domains have been found in about 70 proteins, their precise function is still unclear [ 3,lO121. Many of the proteins possessing a PH domain are involved in signal transduction or cytoskeletal organization, and can be roughly assembled in groups with similar functions. One group plays an important function in regulating the small guanine nucleotide binding proteins such as the GTPase activating protein for p2lras, the pl20GAP, the nucleotide exchange factors specific for p2 lras, SOS, ras-GRF, and other nucleotide exchange factors such as Vav and Dbl. The second group consists of a number of serinelthreonineand tyrosine-specific protein kinases including the protooncoprotein RAC-PK, B-adrenergic receptor kinase (BARK), Nrk AlB, PKCp, Bruton tyrosine kinase (Btk), Tec-A and Tlk [l-3,10,11,13]. Moreover, PH domains are located in the N-terminal regions of the mammalian phospholipase C isoforms [ 121. Other molecules involved in signal transduction that possess PH domains are the insulin receptor substrate 1 IRS-1, the growth factor receptor binding protein GRB-7, and the SH3 binding protein 3BP2. These proteins are located at the cell membrane or are cytosolic proteins that on cellular stimulation are translocated to the membrane. Another group consists of the GTPase dynamin and the cytoskeletal protein B-spectrin. Certain proteins with PH domains, including Dbl, Vav, Bcr and RAC-PK, are proto-oncogenes. The three-dimensional structures of PH domains from pleckstrin [4], /3-spectrin [ S ] and dynamin [6-91 are known. Although the similarity