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Protein domain

This article's citation style may be unclear. The references used may be made clearer with adifferent or consistent style ofcitation,footnoting, orexternal linking.

Pyruvate kinase, a protein from three domains (PDB1pkn)

A protein domain is a part of protein sequence andstructurethat canevolve, function, and existindependently of the rest of the protein chain. Each domain forms a compact three-dimensionalstructure and often can be independently stable andfolded. Many proteins consist of several

structural domains. One domain may appear in a variety of evolutionarily related proteins.

Domains vary in length from between about 25 amino acids up to 500 amino acids in length. The

shortest domains such as zinc fingers are stabilized by metal ions or disulfide bridges. Domainsoften form functional units, such as the calcium-bindingEF hand domainofcalmodulin. Because

they are self-stable, domains can be "swapped" bygenetic engineeringbetween one protein and

another to makechimera proteins.

Contents

[show]

[edit] Background

The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray crystallographicstudies of henlysozyme[1],papain[2]and by limited proteolysis studies ofimmunoglobulins[3][4].

Wetlaufer defined domains as stable units ofprotein structurethat could fold autonomously. In

the past domains have been described as units of:

compact structure[5] function and evolution[6] folding[7].

Each definition is valid and will often overlap, i.e. a compact structural domain that is found

amongst diverse proteins is likely to fold independently within its structural environment. Natureoften brings several domains together to form multidomain and multifunctional proteins with a

vast number of possibilities[8]

. In a multidomain protein, each domain may fulfil its ownfunction independently, or in a concerted manner with its neighbours. Domains can either serve

as modules for building up large assemblies such as virus particles or muscle fibres, or can

provide specific catalytic or binding sites as found in enzymes or regulatory proteins.

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An appropriate example ispyruvate kinase, a glycolytic enzyme that plays an important role in

regulating the flux from fructose-1,6-biphosphate to pyruvate. It contains an all- regulatory

domain, an /-substrate binding domain and an /-nucleotide binding domain, connected by

several polypeptide linkers[9]

(see figure, right). Each domain in this protein occurs in diverse

sets of protein families.

The central /-barrel substrate binding domain is one of the most commonenzymefolds. It is

seen in many different enzyme families catalysing completely unrelated reactions[10]

. The /-barrel is commonly called theTIM barrelnamed after triose phosphate isomerase, which was the

first such structure to be solved[11]

. It is currently classified into 26 homologous families in the

CATH domain database[12]

. The TIM barrel is formed from a sequence of -- motifs closedby the first and last strand hydrogen bonding together, forming an eight stranded barrel. There is

debate about the evolutionary origin of this domain. One study has suggested that a single

ancestral enzyme could have diverged into several families[13]

, while another suggests that a

stable TIM-barrel structure has evolved through convergent evolution[14]

.

The TIM-barrel in pyruvate kinase is 'discontinuous', meaning that more than one segment of thepolypeptide is required to form the domain. This is likely to be the result of the insertion of onedomain into another during the protein's evolution. It has been shown from known structures that

about a quarter of structural domains are discontinuous.[15][16]

The inserted -barrel regulatory

domain is 'continuous', made up of a single stretch of polypeptide.

Covalent association of two domains represents a functional and structural advantage since there

is an increase in stability when compared with the same structures non-covalently associated[17]

.Other, advantages are the protection of intermediates within inter-domain enzymatic clefts that

may otherwise be unstable in aqueous environments, and a fixed stoichiometric ratio of the

enzymatic activity necessary for a sequential set of reactions[18]

.

[edit] Domains are units of protein structure

Main article:Protein structure

[edit] Primary structure

Theprimary structure(string of amino acids) of aproteinencodes its uniquely folded 3D

conformation.[19]

The most important factor governing the folding of a protein into 3D structure

is the distribution of polar and non-polar side chains.[20]

Folding is driven by the burial of

hydrophobic side chains into the interior of the molecule so to avoid contact with the aqueous

environment.

Sequence alignmentis an important tool for determining domains.

[edit] Secondary structure

Generally proteins have a core of hydrophobicresiduessurrounded by a shell of hydrophilic

residues. Since the peptide bonds themselves are polar they are neutralised by hydrogen bonding

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with each other when in the hydrophobic environment. This gives rise to regions of the

polypeptide that form regular 3D structural patterns called 'secondary structure'. There are twomain types of secondary structure:

-helices

-sheet

[edit] Secondary structure motifs

Some simple combinations ofsecondary structureelements have been found to frequently occur

inprotein structureand are referred to as 'super-secondary structure' ormotifs. For example, the

-hairpin motif consists of two adjacent antiparallel -strands joined by a small loop. It is present

in most antiparallel structures both asan isolated ribbon and as part of more complex -sheets.

Another common super-secondary structure is the -- motif, which is frequently used to

connect two parallel -strands. The central -helix connects the C-termini of the first strand tothe N-termini of the second strand, packing its side chains against the -sheet and therefore

shielding the hydrophobic residues of the -strands from the surface.

[edit] Tertiary structure

Several motifs pack together to form compact, local, semi-independent units called

domains.[5]

The overall 3D structure of the polypeptide chain is referred to as the protein's'tertiary structure'. Domains are the fundamental units of tertiary structure, each domain

containing an individual hydrophobic core built from secondary structural units connected by

loop regions. The packing of the polypeptide is usually much tighter in the interior than theexterior of the domain producing a solid-like core and a fluid-like surface.[21]In fact, core

residues are often conserved in a protein family, whereas the residues in loops are less

conserved, unless they are involved in the protein's function. Protein tertiary structure can bedivided into four main classes based on the secondary structural content of the domain .

[22]

All- domains have a domain core built exclusively from -helices. This class isdominated by small folds, many of which form a simple bundle with helices running upand down.

All- domains have a core comprising of antiparallel -sheets, usually two sheets packedagainst each other. Various patterns can be identified in the arrangement of the strands,often giving rise to the identification of recurring motifs, for example the Greek key

motif.[23]

+ domains are a mixture of all- and all- motifs. Classification of proteins into thisclass is difficult because of overlaps to the other three classes and therefore is not used intheCATHdomain database.[12]

/ domains are made from a combination of -- motifs that predominantly form aparallel -sheet surrounded by amphipathic -helices. The secondary structures arearranged in layers or barrels.

Structural alignmentis an important tool for determining domains.

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The majority of genomic proteins, two-thirds in unicellular organisms and more than 80% in

metazoa, are multidomain proteins created as a result of gene duplication events.[32]

Manydomains in multidomain structures could have once existed as independent proteins. More and

more domains in eukaryotic multidomain proteins can be found as independent proteins in

prokaryotes.[33]

For example, vertebrates have a multi-enzyme polypeptide containing theGAR

synthetase,AIR synthetaseandGAR transformylasemodules (GARs-AIRs-GARt; GAR:glycinamide ribonucleotide synthetase/transferase; AIR: aminoimidazole ribonucleotide

synthetase). In insects, the polypeptide appears as GARs-(AIRs)2-GARt, in yeast GARs-AIRs is

encoded separately from GARt, and in bacteria each domain is encoded separately.[34]

[edit] Origin

Multidomain proteins are likely to have emerged from a selective pressure duringevolutionto

create new functions. Various proteins have diverged from common ancestors by different

combinations and associations of domains. Modular units frequently move about, within and

between biological systems through mechanisms of genetic shuffling:

transposition of mobile elements including horizontal transfers (between species);[35] gross rearrangements such as inversions, translocations, deletions and duplications; homologous recombination; slippage ofDNA polymeraseduring replication.

[edit] Difference in proliferation

It is likely that all these and organisms. For example, theABC transporterdomain constitutesone of the largest domain families that appear in all organisms.[34]Many other families that

appear in all organisms show much less proliferation. These include metabolic enzymes and

components of translational apparatus.

[edit] Types of organisation

The simplest multidomain organisation seen in proteins is that of a single domain repeated intandem.[36]The domains may interact with each other or remain isolated, like beads on string.

The giant 30,000 residue muscle proteintitincomprises about 120 fibronectin-III-type and Ig-

type domains.[37]

In the serine proteases, a gene duplication event has led to the formation of a

two -barrel domain enzyme.[38]The repeats have diverged so widely that there is no obvious

sequence similarity between them. The active site is located at a cleft between the two -barreldomains, in which functionally important residues are contributed from each domain.

Genetically engineered mutants of thechymotrypsinserine proteasewere shown to have someproteinase activity even though their active site residues were abolished and it has therefore been

postulated that the duplication event enhanced the enzyme's activity.[38]

[edit] Connectivity

Modules frequently display different connectivity relationships, as illustrated by thekinesinsand

ABC transporters. The kinesin motor domain can be at either end of a polypeptide chain that

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/index.php?title=Protein_domain&action=edit&section=14http://en.wikipedia.org/wiki/DNA_polymerasehttp://en.wikipedia.org/wiki/Homologous_recombinationhttp://en.wikipedia.org/wiki/Protein_domain#cite_note-34http://en.wikipedia.org/wiki/Evolutionhttp://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=13http://en.wikipedia.org/wiki/Protein_domain#cite_note-Henikoff1997-33http://en.wikipedia.org/w/index.php?title=GAR_transformylase&action=edit&redlink=1http://en.wikipedia.org/wiki/AIR_synthetasehttp://en.wikipedia.org/wiki/Phosphoribosylamine-glycine_ligasehttp://en.wikipedia.org/wiki/Phosphoribosylamine-glycine_ligasehttp://en.wikipedia.org/wiki/Protein_domain#cite_note-32http://en.wikipedia.org/wiki/Protein_domain#cite_note-31

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includes a coiled-coil region and a cargo domain.[39]

ABC transporters are built with up to four

domains consisting of two unrelated modules, ATP-binding cassette and an integral membranemodule, arranged in various combinations.

[edit] Domain insertion

Not only do domains recombine, but there are many examples of a domain having been inserted

into another. Sequence or structural similarities to other domains demonstrate that homologuesof inserted and parent domains can exist independently. An example is that of the 'fingers'

inserted into the 'palm' domain within the polymerases of the Pol I family.[40]

[edit] Difference between structural and evolutionary domain

Since a domain can be inserted into another, there should always be at least one continuousdomain in a multidomain protein. This is the main difference between definitions of structural

domains and evolutionary/functional domains. An evolutionary domain will be limited to one or

two connections between domains, whereas structural domains can have unlimited connections,within a given criterion of the existence of a common core. Several structural domains could beassigned to an evolutionary domain.

[edit] Domains are autonomous folding units

[edit] Folding

Main article:protein folding

[edit] History

Protein folding - the unsolved problem Since the seminal work of Anfinsen over forty years

ago,[19]

the goal to completely understand the mechanism by which a polypeptide rapidly folds

into its stable native conformation remains elusive. Many experimental folding studies havecontributed much to our understanding, but the principles that govern protein folding are still

based on those discovered in the very first studies of folding. Anfinsen showed that the native

state of a protein is thermodynamically stable, the conformation being at a global minimum of itsfree energy.

[edit] Folding pathway

Folding is a directed search of conformational space allowing the protein to fold on a

biologically feasible time scale. TheLevinthal paradoxstates that if an averaged sized proteinwould sample all possible conformations before finding the one with the lowest energy, the

whole process would take billions of years.[41]

Proteins typically fold within 0.1 and 1000

seconds, therefore the protein folding process must be directed some way through a specificfolding pathway. The forces that direct this search are likely to be a combination of local and

global influences whose effects are felt at various stages of the reaction .[42]

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Advances in experimental and theoretical studies have shown that folding can be viewed in terms

of energy landscapes,[43][44]

where folding kinetics is considered as a progressive organisation ofan ensemble of partially folded structures through which a protein passes on its way to the folded

structure. This has been described in terms of afolding funnel, in which an unfolded protein has

a large number of conformational states available and there are fewer states available to the

folded protein. A funnel implies that for protein folding there is a decrease in energy and loss ofentropy with increasing tertiary structure formation. The local roughness of the funnel reflects

kinetic traps, corresponding to the accumulation of misfolded intermediates. A folding chain

progresses toward lower intra-chain free-energies by increasing its compactness. The chainsconformational options become increasingly narrowed ultimately toward one native structure.

[edit] Advantage of domains in protein folding

The organisation of large proteins by structural domains represents an advantage for protein

folding, with each domain being able to individually fold, accelerating the folding process and

reducing a potentially large combination of residue interactions. Furthermore, given the observed

random distribution of hydrophobic residues in proteins,[45]

domain formation appears to be theoptimal solution for a large protein to bury its hydrophobic residues while keeping the

hydrophilic residues at the surface.[46][47]

However, the role of inter-domain interactions inprotein folding and in energetics of stabilisation of the native structure, probably differs for each

protein. In T4 lysozyme, the influence of one domain on the other is so strong that the entire

molecule is resistant to proteolytic cleavage. In this case, folding is a sequential process wherethe C-terminal domain is required to fold independently in an early step, and the other domain

requires the presence of the folded C-terminal domain for folding and stabilisation.[48]

It has been found that the folding of an isolated domain can take place at the same rate orsometimes faster than that of the integrated domain.[49]Suggesting that unfavourable interactions

with the rest of the protein can occur during folding. Several arguments suggest that the sloweststep in the folding of large proteins is the pairing of the folded domains.[27]

This is either becausethe domains are not folded entirely correctly or because the small adjustments required for their

interaction are energetically unfavourable,[50]

such as the removal of water from the domain

interface.

[edit] Domains and quaternary structure

[edit] About quaternary structures

Main article:quaternary structure

Many proteins have a quaternary structure, which consists of several polypeptide chains that

associate into an oligomeric molecule. Each polypeptide chain in such a protein is called a

subunit. Hemoglobin, for example, consists of two and two subunits. Each of the four chainshas an all- globin fold with a heme pocket.

[edit] Domain swapping

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Domain swapping is a mechanism for forming oligomeric assemblies.[51]

. In domain swapping, a

secondary or tertiary element of a monomeric protein is replaced by the same element of anotherprotein. Domain swapping can range from secondary structure elements to whole structural

domains. It also represents a model of evolution for functional adaptation by oligomerisation,

e.g. oligomeric enzymes that have their active site at subunit interfaces.[52]

[edit] Domains and protein flexibility

The presence of multiple domains in proteins gives rise to a great deal of flexibility and mobility.

One of the largest observed domain motions is the `swivelling' mechanism inpyruvate phosphate

dikinase. The phosphoinositide domain swivels between two states in order to bring a phosphate

group from the active site of the nucleotide binding domain to that of thephosphoenolpyruvate/pyruvate domain.[53]The phosphate group is moved over a distance of 45A

involving a domain motion of about 100 degrees around a single residue. Domain motions are

important for:[54]

catalysis; regulatory activity; transport of metabolites; formation of protein assemblies and cellular locomotion.

In enzymes, the closure of one domain onto another captures a substrate by an induced fit,

allowing the reaction to take place in a controlled way. Such motions can be observed when two

or more crystallographic 3D structures of a protein are experimentally determined in alternateenvironments, or from the analysis of nuclear magnetic resonance (NMR) derived structures or

from spectra[55]

.measured byneutron spin echo. A detailed analysis by Gerstein led to the

classification of two basic types of domain motion; hinge and shear.[54]Only a relatively smallportion of the chain, namely the inter-domain linker and side chains undergo significant

conformational changes upon domain rearrangement.[56]

[edit] Hinges by secondary structures

A study by Hayward[57]

found that the termini of -helices and -sheets form hinges in a large

number of cases. Many hinges were found to involve two secondary structure elements actinglike hinges of a door, allowing an opening and closing motion to occur. This can arise when two

neighbouring strands within a -sheet situated in one domain, diverge apart as they join the other

domain. The two resulting termini then form the bending regions between the two domains. -

helices that preserve their hydrogen bonding network when bent are found to behave asmechanical hinges, storing `elastic energy' that drives the closure of domains for rapid capture of

a substrate.[57]

[edit] Helical to extended conformation

The interconversion of helical and extended conformations at the site of a domain boundary isnot uncommon. In calmodulin, torsion angles change for five residues in the middle of a domain

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linking -helix. The helix is split into two, almost perpendicular, smaller helices separated by

four residues of an extended strand.[58][59]

[edit] Shear motions

Shear motions involve a small sliding movement of domain interfaces, controlled by the aminoacid side chains within the interface. Proteins displaying shear motions often have a layered

architecture: stacking of secondary structures. The interdomain linker has merely the role ofkeeping the domains in close proximity.

[edit] Domain definition from structural co-ordinates

The importance of domains as structural building blocks and elements of evolution has broughtabout many automated methods for their identification and classification in proteins of known

structure. Automatic procedures for reliable domain assignment is essential for the generation of

the domain databases, especially as the number of protein structures is increasing. Although the

boundaries of a domain can be determined by visual inspection, construction of an automatedmethod is not straightforward. Problems occur when faced with domains that are discontinuous

or highly associated.[60]

The fact that there is no standard definition of what a domain really ishas meant that domain assignments have varied enormously, with each researcher using a unique

set of criteria.[61]

A structural domain is a compact, globular sub-structure with more interactions within it than

with the rest of the protein.[56]

Therefore, a structural domain can be determined by two visual

characteristics; its compactness and its extent of isolation.[62]

Measures of local compactness inproteins have been used in many of the early methods of domain assignment[63][64][65][66]and in

several of the more recent methods.[25][67][68][69][70]

[edit] Considering proteins as small segments

One of the first algorithms[63]

used aC-C distance maptogether with a hierarchical clustering

routine that considered proteins as several small segments, 10 residues in length. The initialsegments were clustered one after another based on inter-segment distances; segments with the

shortest distances were clustered and considered as single segments thereafter. The stepwise

clustering finally included the full protein. Go[66]

also exploited the fact that inter-domaindistances are normally larger than intra-domain distances; all possibleC-C distanceswere

represented as diagonal plots in which there were distinct patterns for helices, extended strands

and combinations of secondary structures.

[edit] Sowdhamini and Blundells method

The method by Sowdhamini and Blundell clusters secondary structures in a protein based on

their C-C distances and identifies domains from the pattern in theirdendrograms.[60]As the

procedure does not consider the protein as a continuous chain of amino acids there are no

problems in treating discontinuous domains. Specific nodes in these dendrograms are identified

http://en.wikipedia.org/wiki/Protein_domain#cite_note-57http://en.wikipedia.org/wiki/Protein_domain#cite_note-57http://en.wikipedia.org/wiki/Protein_domain#cite_note-57http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=30http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=30http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=30http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=31http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=31http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Protein_domain#cite_note-Swindells1995-60http://en.wikipedia.org/wiki/Protein_domain#cite_note-Swindells1995-60http://en.wikipedia.org/wiki/Protein_domain#cite_note-Swindells1995-60http://en.wikipedia.org/wiki/Protein_domain#cite_note-Janin_1983-55http://en.wikipedia.org/wiki/Protein_domain#cite_note-Janin_1983-55http://en.wikipedia.org/wiki/Protein_domain#cite_note-Janin_1983-55http://en.wikipedia.org/wiki/Protein_domain#cite_note-61http://en.wikipedia.org/wiki/Protein_domain#cite_note-61http://en.wikipedia.org/wiki/Protein_domain#cite_note-61http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/wiki/Protein_domain#cite_note-64http://en.wikipedia.org/wiki/Protein_domain#cite_note-64http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67http://en.wikipedia.org/wiki/Protein_domain#cite_note-69http://en.wikipedia.org/wiki/Protein_domain#cite_note-69http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=32http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=32http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=32http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance_map&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance_map&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance_map&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance_map&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance_map&action=edit&redlink=1http://en.wikipedia.org/wiki/Protein_domain#cite_note-Go1978-65http://en.wikipedia.org/wiki/Protein_domain#cite_note-Go1978-65http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=33http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=33http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=33http://en.wikipedia.org/wiki/Dendrogramhttp://en.wikipedia.org/wiki/Dendrogramhttp://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/wiki/Dendrogramhttp://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=33http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance&action=edit&redlink=1http://en.wikipedia.org/wiki/Protein_domain#cite_note-Go1978-65http://en.wikipedia.org/w/index.php?title=C%CE%B1-C%CE%B1_distance_map&action=edit&redlink=1http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=32http://en.wikipedia.org/wiki/Protein_domain#cite_note-69http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-64http://en.wikipedia.org/wiki/Protein_domain#cite_note-64http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/wiki/Protein_domain#cite_note-Crippen_1978-62http://en.wikipedia.org/wiki/Protein_domain#cite_note-61http://en.wikipedia.org/wiki/Protein_domain#cite_note-Janin_1983-55http://en.wikipedia.org/wiki/Protein_domain#cite_note-Swindells1995-60http://en.wikipedia.org/wiki/Protein_domain#cite_note-Sowdhamini1995-59http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=31http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=30http://en.wikipedia.org/wiki/Protein_domain#cite_note-57http://en.wikipedia.org/wiki/Protein_domain#cite_note-57

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as tertiary structural clusters of the protein, these include both super-secondary structures and

domains. The DOMAK algorithm is used to create the 3Dee domain database.[68]

It calculates a'split value' from the number of each type of contact when the protein is divided arbitrarily into

two parts. This split value is large when the two parts of the structure are distinct.

[edit] Method of Wodak and Janin

The method of Wodak and Janin[71]

was based on the calculated interface areas between twochain segments repeatedly cleaved at various residue positions. Interface areas were calculated

by comparing surface areas of the cleaved segments with that of the native structure. Potential

domain boundaries can be identified at a site where the interface area was at a minimum.

Other methods have used measures of solvent accessibility to calculate compactness.[25][72][73]

[edit] PUU algorithm

The PUU algorithm[16]

incorporates a harmonic model used to approximate inter-domaindynamics. The underlying physical concept is that many rigid interactions will occur within eachdomain and loose interactions will occur between domains. This algorithm is used to define

domains in theFSSPdomain database.[67]

[edit] DETECTIVE

Swindells (1995) developed a method, DETECTIVE, for identification of domains in protein

structures based on the idea that domains have a hydrophobic interior. Deficiencies were foundto occur when hydrophobic cores from different domains continue through the interface region.

[edit] Example domains

Armadillo repeats.Named after the -catenin-like Armadillo protein of the fruit flyDrosophila.

Basic Leucine zipper domain (bZIP domain) is found in many DNA-bindingeukaryoticproteins. One part of the domain contains a region that mediates sequence-specific DNA-binding properties and the Leucine zipper that is required for the

dimerizationof two DNA-binding regions. The DNA-binding region comprises a number

of basic aminoacids such asarginineandlysine

Cadherin repeats. Cadherins function as Ca2+-dependent cell-celladhesionproteins.Cadherin domains are extracellular regions which mediate cell-to-cell homophilic

binding between cadherins on the surface of adjacent cells.

Death effector domain(DED) allows protein-protein binding by homotypic interactions(DED-DED).Caspaseproteasestriggerapoptosisvia proteolytic cascades. Pro-Caspase-8

http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=34http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=34http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=34http://en.wikipedia.org/wiki/Protein_domain#cite_note-70http://en.wikipedia.org/wiki/Protein_domain#cite_note-70http://en.wikipedia.org/wiki/Protein_domain#cite_note-70http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-Zehfus_1986-72http://en.wikipedia.org/wiki/Protein_domain#cite_note-Zehfus_1986-72http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=35http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=35http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=35http://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1994-15http://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1994-15http://en.wikipedia.org/wiki/Families_of_structurally_similar_proteinshttp://en.wikipedia.org/wiki/Families_of_structurally_similar_proteinshttp://en.wikipedia.org/wiki/Families_of_structurally_similar_proteinshttp://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1997-66http://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1997-66http://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1997-66http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=36http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=36http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=36http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=37http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=37http://en.wikipedia.org/wiki/Armadillo_repeatshttp://en.wikipedia.org/wiki/Armadillo_repeatshttp://en.wikipedia.org/wiki/Drosophila_melanogasterhttp://en.wikipedia.org/wiki/Drosophila_melanogasterhttp://en.wikipedia.org/wiki/BZIP_domainhttp://en.wikipedia.org/wiki/BZIP_domainhttp://en.wikipedia.org/wiki/BZIP_domainhttp://en.wikipedia.org/wiki/Eukaryotehttp://en.wikipedia.org/wiki/Eukaryotehttp://en.wikipedia.org/wiki/Dimerhttp://en.wikipedia.org/wiki/Dimerhttp://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Lysinehttp://en.wikipedia.org/wiki/Lysinehttp://en.wikipedia.org/wiki/Lysinehttp://en.wikipedia.org/w/index.php?title=Cadherin_repeats&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Cadherin_repeats&action=edit&redlink=1http://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Caspasehttp://en.wikipedia.org/wiki/Caspasehttp://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Caspasehttp://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/w/index.php?title=Cadherin_repeats&action=edit&redlink=1http://en.wikipedia.org/wiki/Lysinehttp://en.wikipedia.org/wiki/Argininehttp://en.wikipedia.org/wiki/Dimerhttp://en.wikipedia.org/wiki/Eukaryotehttp://en.wikipedia.org/wiki/BZIP_domainhttp://en.wikipedia.org/wiki/Drosophila_melanogasterhttp://en.wikipedia.org/wiki/Armadillo_repeatshttp://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=37http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=36http://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1997-66http://en.wikipedia.org/wiki/Families_of_structurally_similar_proteinshttp://en.wikipedia.org/wiki/Protein_domain#cite_note-Holm1994-15http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=35http://en.wikipedia.org/wiki/Protein_domain#cite_note-Zehfus_1986-72http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-Islam1995-24http://en.wikipedia.org/wiki/Protein_domain#cite_note-70http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=34http://en.wikipedia.org/wiki/Protein_domain#cite_note-Siddiqui1995-67

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and pro-caspase-9 bind to specific adaptor molecules via DED domains and this leads to

autoactivation of caspases.

EF hand, ahelix-turn-helixstructural motiffound in eachstructural domainof thesignaling proteincalmodulinand in the muscle proteintroponin-C.

Immunoglobulin-like domains are found in proteins of theimmunoglobulin superfamily(IgSF).[74]They contain about 70-110amino acidsand are classified into different

categories (IgV, IgC1, IgC2 and IgI) according to their size and function. They possess a

characteristic fold in which twobeta sheetsform a sandwich that is stabilized by

interactions between conservedcysteinesand other chargedamino acids. They areimportant for protein-to-protein interactions in processes ofcell adhesion, cell activation,

and molecular recognition. These domains are commonly found in molecules with roles

in theimmune system.

Phosphotyrosine-binding domain(PTB). PTB domains usually bind to phosphorylatedtyrosine residues. They are often found in signal transduction proteins. PTB-domainbinding specificity is determined by residues to the amino-terminal side of the

phosphotyrosine. Examples: the PTB domains of bothSHCandIRS-1bind to aNPXpY

sequence. PTB-containing proteins such as SHC and IRS-1 are important forinsulin

responses of human cells.

Pleckstrin homology domain(PH). PH domains bindphosphoinositideswith highaffinity. Specificity forPtdIns(3)P,PtdIns(4)P,PtdIns(3,4)P2,PtdIns(4,5)P2, and

PtdIns(3,4,5)P3have all been observed. Given the fact that phosphoinositides are

sequestered to various cell membranes (due to their long lipophilic tail) the PH domains

usually causes recruitment of the protein in question to a membrane where the protein can

exert a certain function in cell signalling, cytoskeletal reorganization or membranetrafficking.

Src homology 2 domain(SH2). SH2 domains are often found in signal transductionproteins. SH2 domains confer binding to phosphorylated tyrosine (pTyr). Named after the

phosphotyrosine binding domain of the src viraloncogene, which is itself atyrosinekinase.See also:SH3 domain.

Zinc finger DNA binding domain(ZnF_GATA). ZnF_GATA domain-containingproteins are typicallytranscription factorsthat usually bind to the DNA sequence

[AT]GATA[AG] ofpromoters.

The preceding text and figures originate from "Predicting Structural Domains in Proteins"

George RA, 2002

[edit] See also

Amino acid Binding domain

http://en.wikipedia.org/wiki/EF_handhttp://en.wikipedia.org/wiki/EF_handhttp://en.wikipedia.org/wiki/Helix-turn-helixhttp://en.wikipedia.org/wiki/Helix-turn-helixhttp://en.wikipedia.org/wiki/Structural_motifhttp://en.wikipedia.org/wiki/Structural_motifhttp://en.wikipedia.org/wiki/Structural_motifhttp://en.wikipedia.org/wiki/Structural_domainhttp://en.wikipedia.org/wiki/Structural_domainhttp://en.wikipedia.org/wiki/Structural_domainhttp://en.wikipedia.org/wiki/Signaling_proteinhttp://en.wikipedia.org/wiki/Calmodulinhttp://en.wikipedia.org/wiki/Calmodulinhttp://en.wikipedia.org/wiki/Calmodulinhttp://en.wikipedia.org/wiki/Troponin-Chttp://en.wikipedia.org/wiki/Troponin-Chttp://en.wikipedia.org/wiki/Troponin-Chttp://en.wikipedia.org/wiki/Immunoglobulin_superfamilyhttp://en.wikipedia.org/wiki/Immunoglobulin_superfamilyhttp://en.wikipedia.org/wiki/Immunoglobulin_superfamilyhttp://en.wikipedia.org/wiki/Protein_domain#cite_note-73http://en.wikipedia.org/wiki/Protein_domain#cite_note-73http://en.wikipedia.org/wiki/Protein_domain#cite_note-73http://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Cysteinehttp://en.wikipedia.org/wiki/Cysteinehttp://en.wikipedia.org/wiki/Cysteinehttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/w/index.php?title=Phosphotyrosine-binding_domain&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Phosphotyrosine-binding_domain&action=edit&redlink=1http://en.wikipedia.org/wiki/Src_homology_2_domain-containinghttp://en.wikipedia.org/wiki/Src_homology_2_domain-containinghttp://en.wikipedia.org/wiki/Src_homology_2_domain-containinghttp://en.wikipedia.org/wiki/IRS-1http://en.wikipedia.org/wiki/IRS-1http://en.wikipedia.org/wiki/IRS-1http://en.wikipedia.org/wiki/NPXpYhttp://en.wikipedia.org/wiki/NPXpYhttp://en.wikipedia.org/wiki/NPXpYhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/Pleckstrin_homology_domainhttp://en.wikipedia.org/wiki/Pleckstrin_homology_domainhttp://en.wikipedia.org/wiki/Phosphoinositidehttp://en.wikipedia.org/wiki/Phosphoinositidehttp://en.wikipedia.org/wiki/Phosphoinositidehttp://en.wikipedia.org/wiki/PtdIns(3)Phttp://en.wikipedia.org/wiki/PtdIns(3)Phttp://en.wikipedia.org/wiki/PtdIns(3)Phttp://en.wikipedia.org/w/index.php?title=PtdIns(4)P&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=PtdIns(4)P&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=PtdIns(4)P&action=edit&redlink=1http://en.wikipedia.org/wiki/PtdIns(3,4)P2http://en.wikipedia.org/wiki/PtdIns(3,4)P2http://en.wikipedia.org/wiki/PtdIns(3,4)P2http://en.wikipedia.org/wiki/PtdIns(4,5)P2http://en.wikipedia.org/wiki/PtdIns(4,5)P2http://en.wikipedia.org/wiki/PtdIns(4,5)P2http://en.wikipedia.org/wiki/PtdIns(3,4,5)P3http://en.wikipedia.org/wiki/PtdIns(3,4,5)P3http://en.wikipedia.org/wiki/Src_homology_2_domainhttp://en.wikipedia.org/wiki/Src_homology_2_domainhttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/SH3_domainhttp://en.wikipedia.org/wiki/SH3_domainhttp://en.wikipedia.org/wiki/SH3_domainhttp://en.wikipedia.org/wiki/Zinc_fingerhttp://en.wikipedia.org/wiki/Zinc_fingerhttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/Promoterhttp://en.wikipedia.org/wiki/Promoterhttp://en.wikipedia.org/wiki/Promoterhttp://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=38http://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=38http://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Binding_domainhttp://en.wikipedia.org/wiki/Binding_domainhttp://en.wikipedia.org/wiki/Binding_domainhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/w/index.php?title=Protein_domain&action=edit&section=38http://en.wikipedia.org/wiki/Promoterhttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/Zinc_fingerhttp://en.wikipedia.org/wiki/SH3_domainhttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Tyrosine_kinasehttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/Src_homology_2_domainhttp://en.wikipedia.org/wiki/PtdIns(3,4,5)P3http://en.wikipedia.org/wiki/PtdIns(4,5)P2http://en.wikipedia.org/wiki/PtdIns(3,4)P2http://en.wikipedia.org/w/index.php?title=PtdIns(4)P&action=edit&redlink=1http://en.wikipedia.org/wiki/PtdIns(3)Phttp://en.wikipedia.org/wiki/Phosphoinositidehttp://en.wikipedia.org/wiki/Pleckstrin_homology_domainhttp://en.wikipedia.org/wiki/Insulinhttp://en.wikipedia.org/wiki/NPXpYhttp://en.wikipedia.org/wiki/IRS-1http://en.wikipedia.org/wiki/Src_homology_2_domain-containinghttp://en.wikipedia.org/w/index.php?title=Phosphotyrosine-binding_domain&action=edit&redlink=1http://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Cysteinehttp://en.wikipedia.org/wiki/Beta_sheethttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Protein_domain#cite_note-73http://en.wikipedia.org/wiki/Immunoglobulin_superfamilyhttp://en.wikipedia.org/wiki/Troponin-Chttp://en.wikipedia.org/wiki/Calmodulinhttp://en.wikipedia.org/wiki/Signaling_proteinhttp://en.wikipedia.org/wiki/Structural_domainhttp://en.wikipedia.org/wiki/Structural_motifhttp://en.wikipedia.org/wiki/Helix-turn-helixhttp://en.wikipedia.org/wiki/EF_hand

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CATH Conserved domains Motif domain Protein Protein structure

Protein structure prediction Protein family Structural biology Structural Classification of Proteins(SCOP)

[edit] External links

The Protein Families (Pfam) databaseclan browserprovides easy access to informationabout protein structural domains. A clan contains two or more Pfam families that have

arisen from a single evolutionary origin.

[edit] Structural domain databases

3Dee CATH DALI SCOP Pawson Lab - Protein interaction domains Nash Lab - Protein interaction domains in Signal Transduction Definition and assignment of structural domains in proteins.

[edit] Sequence domain databases

InterPro Pfam PROSITE ProDom SMART NCBI Conserved Domain Database SUPERFAMILYLibrary of HMMs representing superfamilies and database of

(superfamily and family) annotations for all completely sequenced organisms

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