In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an N-glycosylation site motif can be defined as Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro residue.
Overview
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 affinity for specific DNA binding sites bind DNA in only 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.
Motif Representation
Consider the N-glycosylation site motif mentioned above:
Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro 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.
Motifs and consensus sequences 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.
Pattern description notations Several notations for describing motifs are in use but most of them are variants of standard notations for regular expressions and use these conventions:
there is an alphabet of single characters, each denoting a specific amino acid or a set of amino acids; a string of characters drawn from the alphabet denotes a sequence of the corresponding amino acids; any string of characters drawn from the alphabet enclosed in square brackets matches any one of the corresponding amino acids; e.g. [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:
a sequence of elements of the pattern notation matches a sequence of amino acids if and only if the latter sequence can be partitioned into subsequences in such a way that each pattern element matches the corresponding subsequence in turn. 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.
PROSITE pattern notation 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:
The lower case letter 'x' can be used as a pattern element to denote any amino acid. A string of characters drawn from the alphabet and enclosed in braces (curly brackets) denotes any amino acid except for those in the string. For example, {ST} denotes any amino acid other than S or T. If a pattern is restricted to the N-terminal of a sequence, the pattern is prefixed with '<'. If a pattern is restricted to the C-terminal of a sequence, the pattern is suffixed with '>'. The character '>' can also occur inside a terminating square bracket pattern, so that S[T>] matches both "ST" and "S>". If 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)-H
Matrices A 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.
A position frequency matrix (PFM) records the position-dependent frequency of each residue or nucleotide. PFMs can be experimentally determined from SELEX experiments or computationally discovered by tools such as MEME using hidden Markov models. A position weight matrix (PWM) contains log odds weights for computing a match score. A cutoff is needed to specify whether an input sequence matches the motif or not. PWMs are calculated from PFMs. PWMs are also known as PSSMs. An example of a PFM from the TRANSFAC database for the transcription factor AP-1:
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