Sequence motif
Encyclopedia
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 acid
s (see genetic code
).
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 acid
s 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
.
This pattern may be written as
The notation
s. Sometimes patterns are defined in terms of a probabilistic model such as a hidden Markov model
.
For example, the defining sequence for the IQ motif may be taken to be:
where
Usually, however, the first letter is
, 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.
. It spans about 150 amino acid residues, and begins as follows:
Here each
The authors were able to show that the motif has DNA binding activity. PhyloGibbs and the Gibbs Motif Sampler are motif discovery algorithms that consider phylogenetic conservation.
s and use these conventions:
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
Different pattern description notations have other ways of forming pattern elements. One of these notations is the PROSITE notation, described in the following subsection.
notation uses the IUPAC one-letter codes and conforms to the above description with the exception that a concatenation symbol, '
PROSITE allows the following pattern elements in addition to those described previously:
Some examples:
The signature of the C2H2-type zinc finger
domain is:
An example of a PFM from the TRANSFAC
database for the transcription factor AP-1:
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 E. coli lactose operon
repressor LacI ( chain A) and E. coli catabolite gene activator ( 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. 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:
where "
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, a sequence motif is a nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
or amino-acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence
Sequence
In mathematics, a sequence is an ordered list of objects . Like a set, it contains members , and the number of terms is called the length of the sequence. Unlike a set, order matters, and exactly the same elements can appear multiple times at different positions in the sequence...
pattern that is widespread and has, or is conjectured to have, a biological
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
significance. For proteins, a sequence motif is distinguished from a structural motif
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
, a motif formed by the three dimensional arrangement of amino acids, which may not be adjacent.
An example is the N-glycosylation site motif:
- Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro
where the three-letter abbreviations are the conventional designations for amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s (see genetic code
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
).
Overview
When a sequence motif appears in the exonExon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
of a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, it may encode
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
the "structural motif" of a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
; that is a stereotypical element of the overall structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
of the protein. Nevertheless, motifs need not be associated with a distinctive secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
. "Noncoding
Noncoding DNA
In genetics, noncoding DNA describes components of an organism's DNA sequences that do not encode for protein sequences. In many eukaryotes, a large percentage of an organism's total genome size is noncoding DNA, although the amount of noncoding DNA, and the proportion of coding versus noncoding...
" sequences are not translated into proteins, and nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s with such motifs need not deviate from the typical shape (e.g. the "B-form" DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
double helix
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
).
Outside of gene exons, there exist regulatory sequence
Regulatory sequence
A regulatory sequence is a segment of DNA where regulatory proteins such as transcription factors bind preferentially. These regulatory proteins bind to short stretches of DNA called regulatory regions, which are appropriately positioned in the genome, usually a short distance 'upstream' of the...
motifs and motifs within the "junk", such as satellite DNA
Satellite DNA
Satellite DNA consists of very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin....
. Some of these are believed to affect the shape of nucleic acids (see for example RNA self-splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
), 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
Signal sequence
Signal sequence can refer to:*Protein targeting*Signal peptide*DNA uptake signal sequence...
proteins for delivery to particular parts of a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, or mark them for phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
.
Within a sequence or database
Database
A database is an organized collection of data for one or more purposes, usually in digital form. The data are typically organized to model relevant aspects of reality , in a way that supports processes requiring this information...
of sequences, researchers search and find motifs using computer-based techniques of sequence analysis
Sequence analysis
In bioinformatics, the term sequence analysis refers to the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alignment, searches against biological...
, such as BLAST
BLAST
In bioinformatics, Basic Local Alignment Search Tool, or BLAST, is an algorithm for comparing primary biological sequence information, such as the amino-acid sequences of different proteins or the nucleotides of DNA sequences...
. Such techniques belong to the discipline of bioinformatics
Bioinformatics
Bioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...
.
See also consensus sequence
Consensus sequence
In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...
.
Motif bioinformatics
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 logoSequence logo
In bioinformatics, a sequence logo is a graphical representation of the sequence conservation of nucleotides or amino acids .-Logo creation:...
s. Sometimes patterns are defined in terms of a probabilistic model such as a hidden Markov model
Hidden Markov model
A hidden Markov model is a statistical Markov model in which the system being modeled is assumed to be a Markov process with unobserved states. An HMM can be considered as the simplest dynamic Bayesian network. The mathematics behind the HMM was developed by L. E...
.
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.De novo computational discovery of motifs
There are software programs which, given multiple input sequences, attempt to identify one or more candidate motifs. One example is MEMEMeme
A meme is "an idea, behaviour or style that spreads from person to person within a culture."A meme acts as a unit for carrying cultural ideas, symbols or practices, which can be transmitted from one mind to another through writing, speech, gestures, rituals or other imitable phenomena...
, 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.
Discovery through evolutionary conservation
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 and others discovered a pattern which they called the GCM motifGCM transcription factors
In molecular biology, the GCM transcription factors are a family of proteins which contain a GCM motif. The GCM motif is a domain that has been identified in proteins belonging to a family of transcriptional regulators involved in fundamental developmental processes which comprise Drosophila...
. It spans about 150 amino acid residues, and begins as follows:
-
WDIND*.*P..*...D.F.*W***.**.IYS**...A.*H*S*WAMRNTNNHN
Here 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 and the Gibbs Motif Sampler are motif discovery algorithms that consider phylogenetic conservation.
Pattern description notations
Several notations for describing motifs are in use but most of them are variants of standard notations for regular expressionRegular expression
In computing, a regular expression provides a concise and flexible means for "matching" strings of text, such as particular characters, words, or patterns of characters. Abbreviations for "regular expression" include "regex" and "regexp"...
s 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 byaorborc.
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 PROSITEPROSITE
PROSITE is a protein database. It consists of entries describing the protein families, domains and functional sites as well as amino acid patterns, signatures, and profiles in them. These are manually curated by a team of the Swiss Institute of Bioinformatics and tightly integrated into Swiss-Prot...
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 thanSorT. - 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 thatS[T>]matches both "ST" and "S>". - If
eis a pattern element, andmandnare two decimal integers withm<=n, then:-
e(m)is equivalent to the repetition ofeexactlymtimes; -
e(m,n)is equivalent to the repetition ofeexactlyktimes for any integerksatisfying:m<=k<=n.
-
Some examples:
-
x(3)is equivalent tox-x-x. -
x(2,4)matches any sequence that matchesx-xorx-x-xorx-x-x-x.
The signature of the C2H2-type zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
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.
An example of a PFM from the TRANSFAC
TRANSFAC
TRANSFAC is a manually curated database of eukaryotic transcription factors, their genomic binding sites and DNA binding profiles. The contents of the database can be used to predict potential transcription factor binding sites....
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.
Another scheme
The following example comes from the paper by Matsuda, et al. 1997.The E. coli lactose operon
Operon
In genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo trans-splicing to create...
repressor LacI ( chain A) and E. coli catabolite gene activator ( 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. 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.See also
- Biomolecular structure
- Multiple EM for Motif ElicitationMultiple EM for Motif ElicitationMultiple EM for Motif Elicitation or MEME is a tool for discovering motifs in a group of related DNA or protein sequences.A motif is a sequence pattern that occurs repeatedly in a group of related protein or DNA sequences...
- Nucleic acid sequence
- Protein primary structure
- Structural motifStructural motifIn a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
Motif-finding methods
- Minimotif Miner — for discovery of short contiguous motifs of known function (from University of Nevada Las Vegas and University of Connecticut)
- Amadeus and Allegro motif finding platforms (from Tel-Aviv University)
- PROSITE — database of protein families and domains
- Database and Analysis Suite for Quadruplex forming motifs in Nucleotide Sequences
- MEME Suite of motif-based sequence analysis tools
- TRANSFAC — a commercial (limited public access) database for transcription factor motifs
- eMotif (from Stanford University)
- Bioprospector (from Stanford University)
- FIRE motif discovery approach (from the Tavazoie lab at Princeton)
- Cis-analysis — list of and comments on other programs useful for discovering cis-regulatory element motifs
- NCBI Home Page — NIH's National Library of Medicine NCBI (National Center for Biotechnology Information) link to a tremendous number of resources including sequence analysis and motif discovery.
- Transcriptional Regulation Wiki
- Wikiomic Sequence motifs page
Motif-finding Web applications
- BLOCK-maker — finds conserved blocks in a group of two or more unaligned protein sequences
- ELM — functional site prediction of short linear motifs
- FIRE — finds DNA and RNA motifs from expression data using the mutual information
- Gibbs Motif Sampler — discovers overrepresented conserved motifs in an aligned set of orthologous sequences
- GIMSAN — motif-finder with biologically realistic and reliable statistical significance analysis
- Improbizer — searches for motifs in DNA or RNA sequences that occur with improbable frequency
- MEME Suite — discover motifs (highly conserved regions) in groups of related DNA or protein sequences
- Minimotif Miner — public interface to the minimotif miner database which correlates short sequence amino acids to their biological function
- ModuleMaster — allows to search for motifs by pre-defined or custom PWMs
- MotifVoter — variance based ensemble method for discovery of binding sites
- PhyloGibbs — discovers overrepresented conserved motifs in an aligned set of orthologous sequences
- PLACE — database of plant cis-acting regulatory DNA elements
- SCOPE — an ensemble of programs aimed at identifying novel cis-regulatory elements from groups of upstream sequences
- TEIRESIS — search for short sequence motifs in Proteins
- WebMotifs — use different programs to search for DNA-sequence motifs, and to easily combine and evaluate the results
Motif visualization and browsing
- MochiView — a genome browser supporting import of motif libraries and containing tools for motif discovery, visualization, and analysis