Representation of a prediction of the amino acids in tertiary structures of homologues that overlay in three dimensions.
Alignments held by SMART are mostly based on published observations (see domain annotations for details), but are updated and edited manually.

Alignment block

Ungapped alignments that usually represent a single secondary structure.

Bits scores

Alignment scores are reported by HMMer and BLAST as bits scores.
The likelihood that the query sequence is a bona fide homologue of the database sequence is compared to the likelihood that the sequence was instead generated by a "random" model.
Taking the logarithm (to base 2) of this likelihood ratio gives the bits score.

BLAST, Basic local alignment search tool.

An excellent database searching tool developed at the National Center for Biotechnology Information (NCBI) ([1], [2], [3], [4]).
The version of BLAST used in SMART is that of WU-BLAST (WU-BLAST 2.0, W. Gish, 1996, unpublished) that allows gapped alignments. It is not BLASTPGP ([5], [6]).
SMART uses WU-BLAST to search

  1. fully-inclusive sequence databases for homologues of segments of user-supplied sequences

  2. a sequence database that only contains sequences of domains represented in SMART

Cellular Role

Coiled coils

Intimately-associated bundles of long alpha-helices ([1], [2], [3]).
Coiled coils are detected in SMART using the method of Lupas et al. ([4], COILS home).
Coiled coils predictions are indicated on the second line in SMART's graphical output.


Conserved structural entities with distinctive secondary structure content and an hydrophobic core.
In small disulphide-rich and Zn2+-binding or Ca2+- binding domains the hydrophobic core may be provided by cystines and metal ions, respectively.
Homologous domains with common functions usually show sequence similarities.

Domain composition

Proteins with the same domain composition have at least one copy of each of domains of the query.

Domain organisation

Proteins having all the domains as the query in the same order (Additional domains are allowed)).


A WWW-based system that allows easy retrieval of sequence, structure, molecular biology and literature data (Entrez !).
SMART's domain annotation pages contain links to the Entrez system thereby providing extensive literature, structure and sequence information.


This represents the number of sequences with a score greater-than, or equal to, X, expected absolutely by chance.
The E-value connects the score ("X") of an alignment between a user-supplied sequence and a database sequence, generated by any algorithm, with how many alignments with similar or greater scores that would be expected from a search of a random sequence database of equivalent size.
Since version 2.0 E-values are calculated using Hidden Markov Models, leading to more accurate estimates than before.

Extracellular Domains

Domain families that are most prevalent in proteins outside of the cytoplasm and the nucleus.


A position in an alignment that represents a deletion within one sequence relative to another.
Gap penalties are requirements for alignment algorithms in order to reduce excessively-gapped regions.
Gaps in alignments represent insertions that usually occur in protruding loops or beta-bulges within protein structures.

HMM, Hidden Markov model

HMMs are statistical models of the sequence consensus of an homologous family (see the docu).
A particular class of HMMs has been shown to be equivalent to generalised profiles (8867839). Applications of HMMs to sequence analysis are nicely provided by HMMer and SAM.

HMM consensus

The HMM consensus is a 'one line summary' of the corresponding HMM. The amino acid shown for the consensus is the highest probability amino acid at that position according to the HMM. Capital letters mean "highly conserved" residues (probability > 0.5 for protein models).
(modified from the HMMer User's Guide)


The HMMer package ([1], [2]) provides multiple alignment and database searching capabilities.
There are several programs in the package (see the docu) including one (hmmfs) that searches databases for non-overlapping LOCAL similarities (i.e. that match across at least part of the HMM), and another (hmmls) that searches databases for non-overlapping GLOBAL similarities (i.e. that match across the full HMM).
These correspond approximately to profile-based searches using negative and positive profiles, respectively (see WiseTools).
Database searches using hmmls or hmmfs provide alignment scores as bits scores.


Evolutionary descent from a common ancestor due to gene duplication.

Intracellular Domains

Domain families that are most prevalent in proteins within the cytoplasm.


Numbers of domains that are thought from SwissProt annotations to be present in different cellular compartments (cytoplasm, extracellular space, nucleus, and membrane-associated) are shown in annotation pages.


NCBI's Molecular Modeling Database containing X-ray and NMR tertiary structures. SMART's domain annotation pages contain links to the MMDB system.


Sequence motifs are short conserved regions of polypeptides.
Sets of sequence motifs need not necessarily represent homologues.

NRDB, non-redundant database

A database that contains no identical pairs of sequences.


Open reading frame.

Outlier homologues

These are often difficult to detect using HMM methodology. A complementary approach to their detection is to query a database of sequences taken from multiple sequence alignments, using BLAST

This represents a probability that, given a database of a particular size, random sequences score higher than a value X.
P-values are generated by the WU-BLAST algorithm that has been integrated into SMART.

PDB, protein data bank

PDB is an archive of experimentally-determined three-dimensional structures (Brookhaven nat. Labs or EBI).
Domain families represented in SMART and in the PDB are annotated as being of known structure; links are provided in SMART to the PDB via PDBsum and MMDB.
PDBsum links can be used to access a variety of sequence-based and structure-based tools, whereas MMDB provides access to literature information and structure similarities.


Pfam is a database of protein domain families represented as (i) multiple alignments, and (ii) HMM-profiles ([1], [2]).
WWW servers allow comparison of user-supplied sequences with the Pfam database (Sanger Center and Washington Univ.).
SMART contains a facility to search the Pfam collection using HMMer.

prokaryotic domains

SMART now also searches for domains found in two component regulatory systems. These can be found mainly in Prokaryotes, but a few were also found in eukaryotes like yeast and plants.


A profile is a table of position-specific scores and gap penalties, representing an homologous family, that may be used to search sequence databases (Ref.: [1], [2], [3]).
In CLUSTAL-W-derived profiles those sequences that are more distantly related are assigned higher weights ([4], [5], [6]). Issues in profile-based database searching are discussed in Bork & Gibson (1996) [7].


An excellent WWW server that allows a user to compare a protein or DNA sequence against a database of profiles (located at the ISREC).


This is a dictionary of protein sites and motif patterns.
Some SMART domain annotations contain links to PROSITE.

Schnipsel database; domain sequence database

"Schnipsel" is a German word meaning 'snippet' or 'fragment'. The schnipsel database consists of the sequences off all domains found with SMART in NRDB.
Outliers of a family often cannot be detected by a profile, yet are detectable by pairwise similarity to one or more established members of a sequence family. So, searching against the schnipsel database gives complementary information to the profile searches.

Searched domains

In the first version of SMART, only eukaryotic signalling domains could be searched. In 1998 we have extended this set by prokaryotic signalling and extracellular domains. In the input page you can choose wether you only want to search cytoplasmic (prokaryotic + eukaryotic), extracellular or all domains.

Secondary Literature

The secondary literature is derived by the following procedure. For each of the hand selected papers referenced by a domain, 100 neighbouring papers are retrieved using Medline. If one of these neighbouring papers is referenced from more than two original papers, it is included into the secondary literature list.

Seed Alignment

Alignment that contains only one of each pair of homologues that are represented in a CLUSTALW-derived phylogenetic tree linked by a branch of length less than a distance of 0.2 (see the related article).


A program of Wootton & Federhen [1] that detects regions of the query sequence that have low compositional complexity [2].
Low compositional complexity regions predictions are indicated on the second line in SMART's graphical output.

Sequence ID or ACC

Sequence identifiers or accession codes may be entered via the SMART homepage to initiate a query. Identifiers or codes from the following databases are allowed: SwissProt, SwissProtNew, PDB, SpTrembl, SpTremblNew, Trembl, TremblNew and WormPep.

Signalling Domains

The original set of domains used in SMART were collected as those that satisfied one or both of two criteria:

  1. cytoplasmic domains that possess kinase, phosphatase, ubiquitin ligase or phospholipase enzymatic activities or those that stimulate GTPase-activation or guanine nucleotide exchange

  2. cytoplasmic domains that occur in at least two proteins with different domain organisations, of which one also contains a domain that satisfies criterion 1
These domains mostly mediate or regulate the transduction of an extracellular signal towards the nucleus resulting in the initiation of a cellular response.
More recently, prokaryotic two-component signalling domains have been added to the SMART set.


This program predicts the presence and location of signal peptide cleavage sites in amino acid sequences (SignslP home).
SignalP predictions are indicated on the second line in SMART's graphical output.

SMART, Simple Modular Architecture Research Tool

Our main goal in providing this tool is to allow automatic identification and annotation of domains in user-supplied protein sequences.

SwissProt database is an extensively annotated and non-redundant collection of protein sequences.
SwissProt annotations have been mined for SMART-derived annotations of alignments.


This program predicts the location and topology of transmembrane helices (TopPred home).
TopPred predictions are indicated on the second line in SMART's graphical output.


For each of the domains found by SMART a combination of thresholds is used to distinguish between true and false hits. In the input page you can lower these thresholds by some percentage to find weak hits, but false ones will come up. This option is useful if you have some additional information about youre protein that let you assume that a special domain is in it. Use with care.
The different thresholds are described int the SMART paper.


A package that is based on database searches using profiles. Profiles may be generated using PairWise, and then compared with sequence databases using SearchWise.
Scores are generated for alignments that match the whole of the profile (using a "positive" profile) or else that match at least part of the profile (using a "negative" profile). Only the top-scoring optimal alignment of each sequence is reported; hence, SMART relies on re-iterating the search for new repeats until none are reported that score above threshold.
Score thresholds have been set manually that are considered to represent a score just above the top-scoring true negative. Additional thresholds have been estimated for domains that are repeated in single polypeptides.
A more recent package allows comparison of DNA sequences at the level of their conceptual translations, regardless of sequence error and introns (see Wise2).
A new version of WiseTools now reports database searching scores as E-values.