SMART, a simple modular architecture research tool: Identification of signaling domains (computer analysisydiacylglycerol kinasesyDEATH domainydisease genesyautomatic sequence annotation)

TL;DR: SMART as discussed by the authors is a web-based tool that allows rapid identification and annotation of signaling domain sequences, which can be used to determine the modular architectures of single sequences or genomes.

Abstract: Accurate multiple alignments of 86 domains that occur in signaling proteins have been constructed and used to provide a Web-based tool (SMART: simple modular architecture research tool) that allows rapid identification and annotation of signaling domain sequences. The majority of signaling proteins are multidomain in character with a considerable variety of domain combinations known. Com- parison with established databases showed that 25% of our domain set could not be deduced from SwissProt and 41% could not be annotated by Pfam. SMART is able to determine the modular architectures of single sequences or genomes; application to the entire yeast genome revealed that at least 6.7% of its genes contain one or more signaling domains, approximately 350 greater than previously annotated. The process of constructing SMART predicted (i) novel domain homologues in unexpected locations such as band 4.1- homologous domains in focal adhesion kinases; (ii) previously unknown domain families, including a citron-homology do- main; (iii) putative functions of domain families after identi- fication of additional family members, for example, a ubiq- uitin-binding role for ubiquitin-associated domains (UBA); (iv) cellular roles for proteins, such predicted DEATH do- mains in netrin receptors further implicating these molecules in axonal guidance; (v) signaling domains in known disease genes such as SPRY domains in both marenostrinypyrin and Midline 1; (vi) domains in unexpected phylogenetic contexts such as diacylglycerol kinase homologues in yeast and bacte- ria; and (vii) likely protein misclassifications exemplified by a predicted pleckstrin homology domain in a Candida albicans protein, previously described as an integrin.