Focus Issue: Protein Interactions Domains, Zip Codes for Delivery

In the final issue for 2003 of the STKE series on protein interaction domains, Science's STKE focuses on domains implicated in protein trafficking and those that permit protein interaction with membranes. Cell function depends not only on the appropriate expression of proteins, but also on their acting in the right place at the right time. Proper transport of proteins is essential for delivery of proteins to their sites of action as well as for terminating their activity or for rerouting of proteins, which may allow them to gain access to different interacting partners. Protein interactions with membranes, especially through binding to phosphoinositide lipids, provide a mechanism for temporal and spatial regulation of protein activity in response to signals that alter the abundance of these phosphorylated lipids. Similarly, protein interaction domains created through posttranslational modifications allow cell signals to govern the spatial and temporal localization of protein-protein interactions. In the Review by DiNitto et al ., the authors describe several families of lipid-binding motifs and discuss in depth the various structures that allow proteins to interact with phosphoinositides. Major themes of the review are the mechanisms of lipid recognition and how specificity is achieved by the different phosphoinositide-binding domains, which include pleckstrin homology (PH), FYVE (acronym of Fab1, YOTB, Vac1, and EEA1), plant homeodomain (PHD), phox homology (PX), and FERM domains, as well as motifs found in the proteins MARCKS and Tubby. Polo et al . focus on protein networks created through interactions that involve the Eps15 homology (EH) domain, which binds to peptides containing the Asp-Pro-Phe (NPF) motif, and those that depend on monoubiquitination, a posttranslational modification that is emerging as a signaling-dependent device to establish protein-protein interactions. The authors explore the possibility that protein interaction networks involving EH and monoubiquitin (mUb), which were initially implicated in receptor endocytosis and intracellular trafficking, might coordinate to link various processes, including endocytosis and trafficking, control of the actin cytoskeleton, DNA repair, nuclear shuttling, and regulation of the cell cycle. The Review includes extensive supplementary material that classifies and describes known NPF- and ubiquitin (Ub)-binding device [Ub-interacting motif (UIM) and Ub-associated (UBA) domain]-containing proteins. This third issue also includes a Perspective by Stagljar that describes several new techniques for identifying protein partners. Stagljar provides a summary of the methods for the split-ubiquitin membrane yeast two-hybrid system (MbYTH) for detecting interacting membrane proteins, stable isotope labeling by amino acids in cell culture (SILAC) for detecting protein interactions mediated by posttranslational changes (phosphorylation) in target proteins in response to stimulation, target-assisted iterative screening (TAIS) for proteomic analysis of potential binding partners or recognition sequences, and SH2 profiling based on Far Western blotting for analysis of sequence-dependent interactions. The advantages and disadvantages of each of these methods, as well as successful applications of each method for the identification of novel protein interacting partners or characterization of binding sequences, are described. The first issue in the protein interaction domain series featured an overview published in Science by Pawson and Nash describing signaling domains and their function. At STKE (22 April 2003), three Reviews highlighted domains that mediate protein-protein interaction (PDZ domains and domains that bind proline-rich motifs) and domains that mediate RNA binding. Proteins that have RNA binding motifs provide a posttranscriptional layer to the regulation of gene expression in response to various stimuli (see Lasko). The structural basis for the interaction of proteins that bind proline-rich motifs were described and illustrated with animations in Zarrinpar et al . These proline-rich binding domains serve to organize and localize signaling proteins. PDZ domains and their roles in the organization of macromolecular complexes in such cells as neurons and epithelial cells were described by Nourry et al . The second issue in this series (15 July 2003) featured domains that recognize phosphorylated tyrosine residues and those that form a β-propeller structure. Schlessinger and Lemmon described the structural features and differences in the binding characteristics of Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, and also provided an overview of the roles of proteins with these domains in cellular signaling processes. Gettemans et al . described proteins with either WD-40 repeats or kelch repeats that adopt the β-propeller structure. Evidence in yeast suggests that by folding into a β propeller similar to that seen for the heterotrimeric GTP binding protein (G protein) β subunit, kelch-domain proteins may function as one subunit of the heterotrimeric G protein in place of the β subunit in particular signaling cascades. Although this third issue brings the 2003 protein interactions domains series to a close, Science's STKE expects research concerning protein interaction domains--and the targeting of such domains in therapeutic interventions--to have continuing impact on the field of cell signaling and will continue to follow this area as new research unfolds. Featured in This Focus Issue Reviews Perspectives Related Resources at STKE Editorial Guides Reviews Perspectives Teaching Resources Virtual Journal ST on the Web