domains cannot be deduced from the current yeast genome directory (8) and no human RasGEF domains currently are annotated in SwissProt. Graphical representation of the complement of modular proteins in a completed genome (e.g., the 622 signaling domains in 420 yeast proteins: http://www.bork.embl-heidelberg.de/Modules/syeast.html) might provide the basis for relating experimentally derived information concerning domains and multidomain proteins, to cellular events such as signaling.

Although other collections, such as PROSITE, Pfam, BLOCKS, and PRINTS, contain many more distinct domains or motifs, the focus of SMART on signaling allows significantly enhanced detection sensitivity, the inclusion of many families that are not represented in other collections, and offers a high level of specificity (i.e., a low rate of false positives that is essential for large-scale analysis). The SMART database shall be continually updated; alignment updates shall be semiautomated to avoid misalignments. Thus, forthcoming SMART database versions shall be hand-checked to provide datasets of high quality. In future, experimental findings that advance the understanding of domain structure and function also shall be provided via updates. As SMART is designed to obtain biologically relevant results without dependency on a single database search technique, there is potential to modify underlying methods to improve performance.

Note Added in Proof. Recent improvements to the SMART system include implementation of SWise-derived E-values and addition of more than 80 extracellular domains. A ProfileScan Server (http://ulrec3.unil.ch/software/PFSCAN_form.html) has appeared recently that includes facilities that are similar or complementary to those of SMART.

We thank colleagues at the European Molecular Biology Laboratory and Ewan Birney for many helpful discussions. We also thank Bemhard Sulzer for computational assistance. C.P.P. is a Wellcome Trust Career Development Fellow and a member of the Oxford Centre for Molecular Sciences, and was supported in part by a European Molecular Biology Organization Short-Term Fellowship. J.S. and P.B were supported by the European Union, Bundesministerium für Bildung und Forschung (Germany), and the Deutsche Forschungsgemeinschaft.

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