In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance. For proteins, a sequence motif is distinguished from a structural motif, a motif formed by the three dimensional arrangement of amino acids, which may not be adjacent.
An example is the N-glycosylation site motif:
where the three-letter abbreviations are the conventional designations for amino acids (see genetic code).
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When a sequence motif appears in the exon of a gene, it may encode the "structural motif" of a protein; that is a stereotypical element of the overall structure of the protein. Nevertheless, motifs need not be associated with a distinctive secondary structure. "Noncoding" sequences are not translated into proteins, and nucleic acids with such motifs need not deviate from the typical shape (e.g. the "B-form" DNA double helix).
Outside of gene exons, there exist regulatory sequence motifs and motifs within the "junk", such as satellite DNA. Some of these are believed to affect the shape of nucleic acids (see for example RNA self-splicing), but this is only sometimes the case. For example, many DNA binding proteins that have affinities for specific motifs only bind DNA in its double-helical form. They are able to recognize motifs through contact with the double helix's major or minor groove.
Short coding motifs, which appear to lack secondary structure, include those that label proteins for delivery to particular parts of a cell, or mark them for phosphorylation.
Within a sequence or database of sequences, researchers search and find motifs using computer-based techniques of sequence analysis, such as BLAST. Such techniques belong to the discipline of bioinformatics.
See also consensus sequence.
Consider the N-glycosylation site motif mentioned above:
This pattern may be written as N{P}[ST]{P} where N = Asn, P = Pro, S = Ser, T = Thr; {X} means any amino acid except X; and [XY] means either X or Y.
The notation [XY] does not give any indication of the probability of X or Y occurring in the pattern. Observed probabilities can be graphically represented using sequence_logos. Sometimes patterns are defined in terms of a probabilistic model such as a hidden Markov model.
The notation [XYZ] means X or Y or Z, but does not indicate the likelihood of any particular match. For this reason, two or more patterns are often associated with a single motif: the defining pattern, and various typical patterns.
For example, the defining sequence for the IQ motif may be taken to be:
[FILV]Qxxx[RK]Gxxx[RK]xx[FILVWY]where x signifies any amino acid, and the square brackets indicate an alternative (see below for further details about notation).
Usually, however, the first letter is I, and both [RK] choices resolve to R. Since the last choice is so wide, the pattern IQxxxRGxxxR is sometimes equated with the IQ motif itself, but a more accurate description would be a consensus sequence for the IQ motif.
There are software programs which, given multiple input sequences, attempt to identify one or more candidate motifs. One example is MEME, which generates statistical information for each candidate. Other algorithms include AlignAce, Amadeus, CisModule, FIRE, Gibbs Motif Sampler, PhyloGibbs, and Weeder. SCOPE is an ensemble motif finder that uses several algorithms simultaneously. There currently exist more than 100 publications with similar algorithms without a comprehensive benchmark so selecting one is not straightforward.
Motifs have been discovered by studying similar genes in different species. For example, by aligning the amino acid sequences specified by the GCM (glial cells missing) gene in man, mouse and D. melanogaster, Akiyama[1] and others discovered a pattern which they called the GCM motif. It spans about 150 amino acid residues, and begins as follows:
WDIND*.*P..*...D.F.*W***.**.IYS**...A.*H*S*WAMRNTNNHNHere each . signifies a single amino acid or a gap, and each * indicates one member of a closely related family of amino acids.
The authors were able to show that the motif has DNA binding activity. PhyloGibbs[2][3] and the Gibbs Motif Sampler[4][5] are motif discovery algorithms that consider phylogenetic conservation.
Several notations for describing motifs are in use but most of them are variants of standard notations for regular expressions and use these conventions:
[abc] matches any of the amino acids represented by a or b or c.The fundamental idea behind all these notations is the matching principle, which assigns a meaning to a sequence of elements of the pattern notation:
Thus the pattern [AB] [CDE] F matches the six amino acid sequences corresponding to ACF, ADF, AEF, BCF, BDF, and BEF.
Different pattern description notations have other ways of forming pattern elements. One of these notations is the PROSITE notation, described in the following subsection.
The PROSITE notation uses the IUPAC one-letter codes and conforms to the above description with the exception that a concatenation symbol, '-', is used between pattern elements, but it is often dropped between letters of the pattern alphabet.
PROSITE allows the following pattern elements in addition to those described previously:
x' can be used as a pattern element to denote any amino acid.{ST} denotes any amino acid other than S or T.<'.>'.>' can also occur inside a terminating square bracket pattern, so that S[T>] matches both "ST" and "S>".e is a pattern element, and m and n are two decimal integers with m <= n, then:
e(m) is equivalent to the repetition of e exactly m times;e(m,n) is equivalent to the repetition of e exactly k times for any integer k satisfying: m <= k <= n.Some examples:
x(3) is equivalent to x-x-x.x(2,4) matches any sequence that matches x-x or x-x-x or x-x-x-x.The signature of the C2H2-type zinc finger domain is:
C-x(2,4)-C-x(3)-[LIVMFYWC]-x(8)-H-x(3,5)-HA matrix of numbers containing scores for each residue or nucleotide at each position of a fixed-length motif. There are two types of weight matrices.
An example of a PFM from the TRANSFAC database for the transcription factor AP-1:
| Pos | A | C | G | T | IUPAC |
|---|---|---|---|---|---|
| 01 | 6 | 2 | 8 | 1 | R |
| 02 | 3 | 5 | 9 | 0 | S |
| 03 | 0 | 0 | 0 | 17 | T |
| 04 | 0 | 0 | 17 | 0 | G |
| 05 | 17 | 0 | 0 | 0 | A |
| 06 | 0 | 16 | 0 | 1 | C |
| 07 | 3 | 2 | 3 | 9 | T |
| 08 | 4 | 7 | 2 | 4 | N |
| 09 | 9 | 6 | 1 | 1 | M |
| 10 | 4 | 3 | 7 | 3 | N |
| 11 | 6 | 3 | 1 | 7 | W |
The first column specifies the position, the second column contains the number of occurrences of A at that position, the third column contains the number of occurrences of C at that position, the fourth column contains the number of occurrences of G at that position, the fifth column contains the number of occurrences of T at that position, and the last column contains the IUPAC notation for that position. Note that the sums of occurrences for A, C, G, and T for each row should be equal because the PFM is derived from aggregating several consensus sequences.
The following example comes from the paper by Matsuda, et al. 1997.[6]
The E. coli lactose operon repressor LacI (PDB 1lcc chain A) and E. coli catabolite gene activator (PDB 3gap chain A) both have a helix-turn-helix motif, but their amino acid sequences do not show much similarity, as shown in the table below.
Matsuda, et al.[6] devised a code they called the "three-dimensional chain code" for representing a protein structure as a string of letters. This encoding scheme reveals the similarity between the proteins much more clearly than the amino acid sequence:
| 3D chain code | Amino acid sequence | |
|---|---|---|
| 1lccA | TWWWWWWWKCLKWWWWWWG |
LYDVAEYAGVSYQTVSRVV |
| 3gapA | KWWWWWWGKCFKWWWWWWW |
RQEIGQIVGCSRETVGRIL |
where "W" corresponds to an α-helix, and "E" and "D" correspond to a β-strand.