Comparative Sequence Analysis   

Overview

Accurate multiple alignments of 86 domains that occur in signalling 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 signalling domain sequences.

The majority of signalling proteins are multidomain in character with a considerable variety of domain combinations known.

Comparison with established collections of domain patterns and alignments showed that 25% of our domain set could not be deduced from sequence database entries 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 signalling domains, approximately 350 greater than previously annotated.

The process of constructing the search tool predicted

1. additional homologues of previously-described domains in unexpected locations such as a band 4.1-homologous domain in focal adhesion kinase;

2. previously-unknown domain families including a "CNH" or citron-homology domain and a domain preceeding rasGEF-like guanine nucleotide exchange factor regions;

3. candidate functions of domain families following identification of additional family members, for example, a ubiquitin-binding role for the UBA domain;

4. cellular roles for proteins, such as the detection of a DEATH domain in netrin receptors further implicating these molecules in axonal guidance;

5. signalling domains in known disease genes such as a SPRY domain in marenostrin/pyrin that is mutated in patients with Mediterranean fever;

6. domains in unexpected phylogenetic contexts such as DAG kinase homologues in yeast and bacteria;

7. likely misclassifications of proteins exemplified by the presence of a pleckstrin homology signalling domain in a C. albicans protein, previously described as an integrin.

For all the details, please refer to the publication on SMART:

Schultz,J., Milpetz,F., Bork,P. & Ponting,C.P. (1998).
SMART, a simple modular architecture research tool: Identification of signaling domains. PNAS, 95, 5857-5864

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