NeW Wrinkles for an Old Domain

The fragment of Prp40p spanning its two WW domains bound to phosphorylated CTD of RNA Pol II efficiently, whereas the Rsp5p WW domain region had a capacity to interact with both the phosphor-WW domains are protein–protein interaction modules ylated and unphosphorylated CTD, showing a clear pref-that bind to short proline-rich motifs in proteins that erence for the latter (Wang et al., 1999; Chang et al., operate in a variety of signaling pathways. Because sev-2000; Morris and Greenleaf, 2000). The WW domain thus eral of the cognate, proline-rich motifs are terminated joins a group of modules that can bind protein ligands by a conserved and potentially phosphorylatable tyrosine, in a phosphorylation-dependent manner, including SH2, it has been suggested that protein–protein interactions PTB, 14-3-3, WD40, FHA, and FF domains. mediated by some WW domains might be modulated This unexpected property of the WW domains of Pin1/ by phosphorylation. Moreover, recent data show that Ess1p, Prp40p, and Nedd4 family proteins correlates some WW domains require phosphorylation of the li-with the proposed function of these proteins. Pin1 can gand for binding, specifically, phosphorylation of serine regulate early mitotic events through interaction with or threonine in Ser-Pro or Thr-Pro containing ligands. several mitosis-specific phosphoproteins including the The recent high-resolution structures of WW domain Cdc25C phosphatase, and the Myt1 and Plk1 protein complexes have provided molecular details explaining kinases (Shen et al., 1998; Lu et al., 1999a). The Pin1 how WW domains recognize diverse and modified se-PPIase acts on p-Ser/Thr-Pro bonds (Shen et al., 1998). quence motifs. In addition, these structures showed that Isomerization of this bond may alter local or global pro-in certain details of protein ligand binding the WW do-tein conformation and thereby regulate function (e.g., main is more similar to the SH3 domain than was origi-inhibition of Cdc25C phosphatase activity) or facilitate nally thought. This minireview focuses on recent data sug-dephosphorylation by PP2A, which requires the bond gesting that in some cases ligand phosphorylation may to be in the trans conformation. Interestingly, the Pin1 serve as a switch that regulates WW domain-ligand WW domain can only bind p-Ser-Pro peptides in the complexes. trans conformation, and it may be used to select targets The WW domain is one of the smallest protein mod-for isomerization and/or stabilize p-Ser-Pro bonds for ules that folds as a monomer in solution without disulfide subsequent dephosphorylation. Ess1p, the budding bridges or cofactors. Its 40 amino acids form a compact …