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Vol. 95, Issue 11, 5857-5864, May 26, 1998 (computer analysis / diacylglycerol
kinases / DEATH domain / disease genes / automatic
sequence annotation)
* European Molecular Biology Laboratory, Meyerhofstr.1, 69012 Heidelberg, Germany;
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. Comparison 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 domain; (iii)
putative functions of domain families after identification of
additional family members, for example, a ubiquitin-binding role for
ubiquitin-associated domains (UBA); (iv) cellular roles
for proteins, such predicted DEATH domains in netrin receptors further
implicating these molecules in axonal guidance; (v)
signaling domains in known disease genes such as SPRY domains in both
marenostrin/pyrin and Midline 1; (vi) domains in
unexpected phylogenetic contexts such as diacylglycerol kinase homologues in yeast and bacteria; and (vii)
likely protein misclassifications exemplified by a predicted pleckstrin
homology domain in a Candida albicans protein,
previously described as an integrin.
Copyright © 1998 by The National Academy of Sciences 0027-8424/98/955857-8$2.00/0
This paper was presented at the colloquium "Computational
Biomolecular Science," organized by Russell Doolittle, J. Andrew
McCammon, and Peter G. Wolynes, held September 11-13, 1997, sponsored
by the National Academy of Sciences at the Arnold and Mabel Beckman
Center in Irvine, CA.
Colloquium Paper
SMART, a simple modular architecture research tool:
Identification of signaling domains
,,,
, and Max-Delbrunk-Center for Molecular
Medicine, Robert-Rössle-Str 10, 13122, Berlin, Germany; and
§ University of Oxford, The Old Observatory, South Parks Road,
Oxford OX1 3RH, United Kingdom
To whom reprint requests should be addressed.
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