Protein domain

Pyruvate kinase, a protein with three domains (PDB: 1PKN).

A protein domain is a conserved part of a given protein sequence and (tertiary) structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural domains. One domain may appear in a variety of different proteins. Molecular evolution uses domains as building blocks and these may be recombined in different arrangements to create proteins with different functions. 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. Domains often form functional units, such as the calcium-binding EF hand domain of calmodulin. Because they are independently stable, domains can be "swapped" by genetic engineering between one protein and another to make chimeric proteins.


The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray crystallographic studies of hen lysozyme [1] and papain [2] and by limited proteolysis studies of immunoglobulins.[3][4] Wetlaufer defined domains as stable units of protein structure that could fold autonomously. In the past domains have been described as units of:

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. Nature often brings several domains together to form multidomain and multifunctional proteins with a vast number of possibilities.[8] In a multidomain protein, each domain may fulfill its own function 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.

An appropriate example is pyruvate kinase (see first figure), a glycolytic enzyme that plays an important role in regulating the flux from fructose-1,6-biphosphate to pyruvate. It contains an all-β nucleotide binding domain (in blue), an α/β-substrate binding domain (in grey) and an α/β-regulatory domain (in olive green),[9] connected by several polypeptide linkers.[10] Each domain in this protein occurs in diverse sets of protein families.

The central α/β-barrel substrate binding domain is one of the most common enzyme folds. It is seen in many different enzyme families catalysing completely unrelated reactions.[11] The α/β-barrel is commonly called the TIM barrel named after triose phosphate isomerase, which was the first such structure to be solved.[12] It is currently classified into 26 homologous families in the CATH domain database.[13] The TIM barrel is formed from a sequence of β-α-β motifs closed by 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,[14] while another suggests that a stable TIM-barrel structure has evolved through convergent evolution.[15]

The TIM-barrel in pyruvate kinase is 'discontinuous', meaning that more than one segment of the polypeptide is required to form the domain. This is likely to be the result of the insertion of one domain into another during the protein's evolution. It has been shown from known structures that about a quarter of structural domains are discontinuous.[16][17] The inserted β-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.[18] 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.[19]

Units of protein structure

Main article: Protein structure

The primary structure (string of amino acids) of a protein ultimately encodes its uniquely folded three-dimensional (3D) conformation.[20] The most important factor governing the folding of a protein into 3D structure is the distribution of polar and non-polar side chains.[21] Folding is driven by the burial of hydrophobic side chains into the interior of the molecule so to avoid contact with the aqueous environment. Generally proteins have a core of hydrophobic residues surrounded by a shell of hydrophilic residues. Since the peptide bonds themselves are polar they are neutralised by hydrogen bonding 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 two main types of secondary structure: α-helices and β-sheets.

Some simple combinations of secondary structure elements have been found to frequently occur in protein structure and are referred to as supersecondary structure or motifs. For example, the β-hairpin motif consists of two adjacent antiparallel β-strands joined by a small loop. It is present in most antiparallel β structures both as an isolated ribbon and as part of more complex β-sheets. Another common super-secondary structure is the β-α-β motif, which is frequently used to connect two parallel β-strands. The central α-helix connects the C-termini of the first strand to the N-termini of the second strand, packing its side chains against the β-sheet and therefore shielding the hydrophobic residues of the β-strands from the surface.

Structural alignment is an important tool for determining domains.

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 the exterior of the domain producing a solid-like core and a fluid-like surface.[22] 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 be divided into four main classes based on the secondary structural content of the domain.[23]

Limits on size

Domains have limits on size.[25] The size of individual structural domains varies from 36 residues in E-selectin to 692 residues in lipoxygenase-1,[16] but the majority, 90%, have less than 200 residues[26] with an average of approximately 100 residues.[27] Very short domains, less than 40 residues, are often stabilised by metal ions or disulfide bonds. Larger domains, greater than 300 residues, are likely to consist of multiple hydrophobic cores.[28]

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 α and two β subunits. Each of the four chains has an all-α globin fold with a heme pocket.

Domain swapping is a mechanism for forming oligomeric assemblies.[29] In domain swapping, a secondary or tertiary element of a monomeric protein is replaced by the same element of another protein. 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.[30]

Domains as evolutionary modules

Nature is a tinkerer and not an inventor,[31] new sequences are adapted from pre-existing sequences rather than invented. Domains are the common material used by nature to generate new sequences; they can be thought of as genetically mobile units, referred to as 'modules'. Often, the C and N termini of domains are close together in space, allowing them to easily be "slotted into" parent structures during the process of evolution. Many domain families are found in all three forms of life, Archaea, Bacteria and Eukarya.[32] Domains that are repeatedly found in diverse proteins are often referred to as modules; examples can be found among extracellular proteins associated with clotting, fibrinolysis, complement, the extracellular matrix, cell surface adhesion molecules and cytokine receptors.[33]

Molecular evolution gives rise to families of related proteins with similar sequence and structure. However, sequence similarities can be extremely low between proteins that share the same structure. Protein structures may be similar because proteins have diverged from a common ancestor. Alternatively, some folds may be more favored than others as they represent stable arrangements of secondary structures and some proteins may converge towards these folds over the course of evolution. There are currently about 110,000 experimentally determined protein 3D structures deposited within the Protein Data Bank (PDB).[34] However, this set contains many identical or very similar structures. All proteins should be classified to structural families to understand their evolutionary relationships. Structural comparisons are best achieved at the domain level. For this reason many algorithms have been developed to automatically assign domains in proteins with known 3D structure; see 'Domain definition from structural co-ordinates'.

The CATH domain database classifies domains into approximately 800 fold families; ten of these folds are highly populated and are referred to as 'super-folds'. Super-folds are defined as folds for which there are at least three structures without significant sequence similarity.[35] The most populated is the α/β-barrel super-fold, as described previously.

Multidomain proteins

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.[36] Many domains 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.[37] For example, vertebrates have a multi-enzyme polypeptide containing the GAR synthetase, AIR synthetase and GAR transformylase modules (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.[38]


Multidomain proteins are likely to have emerged from selective pressure during evolution to 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:

Types of organization

Insertions of similar PH domain modules (maroon) into two different proteins.

The simplest multidomain organization seen in proteins is that of a single domain repeated in tandem.[40] The domains may interact with each other (domain-domain interaction) or remain isolated, like beads on string. The giant 30,000 residue muscle protein titin comprises about 120 fibronectin-III-type and Ig-type domains.[41] In the serine proteases, a gene duplication event has led to the formation of a two β-barrel domain enzyme.[42] 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 β-barrel domains, in which functionally important residues are contributed from each domain. Genetically engineered mutants of the chymotrypsin serine protease were shown to have some proteinase activity even though their active site residues were abolished and it has therefore been postulated that the duplication event enhanced the enzyme's activity.[42]

Modules frequently display different connectivity relationships, as illustrated by the kinesins and ABC transporters. The kinesin motor domain can be at either end of a polypeptide chain that includes a coiled-coil region and a cargo domain.[43] ABC transporters are built with up to four domains consisting of two unrelated modules, ATP-binding cassette and an integral membrane module, arranged in various combinations.

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 homologues of 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.[44] Since a domain can be inserted into another, there should always be at least one continuous domain 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 be assigned to an evolutionary domain.

A superdomain consists of two or more conserved domains of nominally independent origin, but subsequently inherited as a single structural/functional unit.[45] This combined superdomain can occur in diverse proteins that are not related by gene duplication alone. An example of a superdomain is the protein tyrosine phosphataseC2 domain pair in PTEN, tensin, auxilin and the membrane protein TPTE2. This superdomain is found in proteins in animals, plants and fungi. A key feature of the PTP-C2 superdomain is amino acid residue conservation in the domain interface.

Domains are autonomous folding units


Further information: Protein folding

Protein folding - the unsolved problem : Since the seminal work of Anfinsen in the early 1960s,[20] the goal to completely understand the mechanism by which a polypeptide rapidly folds into its stable native conformation remains elusive. Many experimental folding studies have contributed 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 its free energy.

Folding is a directed search of conformational space allowing the protein to fold on a biologically feasible time scale. The Levinthal paradox states that if an averaged sized protein would sample all possible conformations before finding the one with the lowest energy, the whole process would take billions of years.[46] Proteins typically fold within 0.1 and 1000 seconds. Therefore, the protein folding process must be directed some way through a specific folding 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.[47]

Advances in experimental and theoretical studies have shown that folding can be viewed in terms of energy landscapes,[48][49] where folding kinetics is considered as a progressive organisation of an ensemble of partially folded structures through which a protein passes on its way to the folded structure. This has been described in terms of a folding 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 of entropy 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 chain's conformational options become increasingly narrowed ultimately toward one native structure.

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,[50] domain formation appears to be the optimal solution for a large protein to bury its hydrophobic residues while keeping the hydrophilic residues at the surface.[51][52]

However, the role of inter-domain interactions in protein 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 where the 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.[53]

It has been found that the folding of an isolated domain can take place at the same rate or sometimes faster than that of the integrated domain,[54] suggesting that unfavourable interactions with the rest of the protein can occur during folding. Several arguments suggest that the slowest step in the folding of large proteins is the pairing of the folded domains.[28] This is either because the domains are not folded entirely correctly or because the small adjustments required for their interaction are energetically unfavourable,[55] such as the removal of water from the domain interface.

Domains and protein flexibility

Main: Protein domain dynamics.

Protein domain dynamics play a key role in a multitude of molecular recognition and signaling processes. Protein domains, connected by intrinsically disordered flexible linker domains, induce long-range allostery via protein domain dynamics. The resultant dynamic modes cannot be generally predicted from static structures of either the entire protein or individual domains.

Domain definition from structural co-ordinates

The importance of domains as structural building blocks and elements of evolution has brought about 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 known protein structures is increasing. Although the boundaries of a domain can be determined by visual inspection, construction of an automated method is not straightforward. Problems occur when faced with domains that are discontinuous or highly associated.[56] The fact that there is no standard definition of what a domain really is has meant that domain assignments have varied enormously, with each researcher using a unique set of criteria.[57]

A structural domain is a compact, globular sub-structure with more interactions within it than with the rest of the protein.[58] Therefore, a structural domain can be determined by two visual characteristics: its compactness and its extent of isolation.[59] Measures of local compactness in proteins have been used in many of the early methods of domain assignment[60][61][62][63] and in several of the more recent methods.[26][64][65][66][67]


One of the first algorithms[60] used a Cα-Cα distance map together with a hierarchical clustering routine that considered proteins as several small segments, 10 residues in length. The initial segments 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[63] also exploited the fact that inter-domain distances are normally larger than intra-domain distances; all possible Cα-Cα distances were represented as diagonal plots in which there were distinct patterns for helices, extended strands and combinations of secondary structures.

The method by Sowdhamini and Blundell clusters secondary structures in a protein based on their Cα-Cα distances and identifies domains from the pattern in their dendrograms.[56] 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 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.[65] 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.

The method of Wodak and Janin[68] was based on the calculated interface areas between two chain 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.[26][69][70]

The PUU algorithm[17] incorporates a harmonic model used to approximate inter-domain dynamics. The underlying physical concept is that many rigid interactions will occur within each domain and loose interactions will occur between domains. This algorithm is used to define domains in the FSSP domain database.[64]

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 found to occur when hydrophobic cores from different domains continue through the interface region.

RigidFinder is a novel method for identification of protein rigid blocks (domains and loops) from two different conformations. Rigid blocks are defined as blocks where all inter residue distances are conserved across conformations.

A general method to identify dynamical domains, that is protein regions that behave approximately as rigid units in the course of structural fluctuations, has been introduced by Potestio et al.[71] and, among other applications was also used to compare the consistency of the dynamics-based domain subdivisions with standard structure-based ones. The method, termed PiSQRD, is publicly available in the form of a webserver.[72] The latter allows users to optimally subdivide single-chain or multimeric proteins into quasi-rigid domains[71][72] based on the collective modes of fluctuation of the system. By default the latter are calculated through an elastic network model;[73] alternatively pre-calculated essential dynamical spaces can be uploaded by the user.

Example domains

Domains of unknown function

A large fraction of domains are of unknown function. A domain of unknown function (DUF) is a protein domain that has no characterized function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. There are now over 3,000 DUF families within the Pfam database representing over 20% of known families.[75]

See also


This article incorporates text and figures from George, R. A. (2002) "Predicting Structural Domains in Proteins" Thesis, University College London, which were contributed by its author.

  1. Phillips DC. (1966). "The three-dimensional structure of an enzyme molecule". Scientific American. 215 (5): 78–90. doi:10.1038/scientificamerican1166-78. PMID 5978599.
  2. Drenth J, Jansonius JN, Koekoek R, Swen HM, Wolthers BG.; Jansonius; Koekoek; Swen; Wolthers (1968). "Structure of papain". Nature. 218 (5145): 929–32. Bibcode:1968Natur.218..929D. doi:10.1038/218929a0. PMID 5681232.
  3. Porter RR. (1973). "Structural studies of immunoglobulins". Science. 180 (4087): 713–6. Bibcode:1973Sci...180..713P. doi:10.1126/science.180.4087.713. PMID 4122075.
  4. Edelman GM. (1973). "Antibody structure and molecular immunology". Science. 180 (4088): 830–40. Bibcode:1973Sci...180..830E. doi:10.1126/science.180.4088.830. PMID 4540988.
  5. 1 2 Richardson J. S. (1981). "The anatomy and taxonomy of protein structure". Adv Protein Chem. 34: 167–339. doi:10.1016/S0065-3233(08)60520-3. PMID 7020376.
  6. Bork P. (1991). "Shuffled domains in extracellular proteins". FEBS Lett. 286 (1–2): 47–54. doi:10.1016/0014-5793(91)80937-X. PMID 1864378.
  7. Wetlaufer DB. (1973). "Nucleation, rapid folding, and globular intrachain regions in proteins". Proc Natl Acad Sci USA. 70 (3): 697–701. Bibcode:1973PNAS...70..697W. doi:10.1073/pnas.70.3.697. PMC 433338Freely accessible. PMID 4351801.
  8. Chothia C. (1992). "Proteins. One thousand families for the molecular biologist". Nature. 357 (6379): 543–4. Bibcode:1992Natur.357..543C. doi:10.1038/357543a0. PMID 1608464.
  9. Bakszt, Rebecca; Wernimont, Amy; Allali-Hassani, Abdellah; Mok, Man Wai; Hills, Tanya; Hui, Raymond; Pizarro, Juan C.; Gay, Nick (14 September 2010). "The Crystal Structure of Toxoplasma gondii Pyruvate Kinase 1". PLoS ONE. 5 (9): 3. doi:10.1371/journal.pone.0012736. PMC 2939071Freely accessible. PMID 20856875. Retrieved 7 November 2014.
  10. George RA, Heringa J.; Heringa (2002). "An analysis of protein domain linkers: their classification and role in protein folding". Protein Eng. 15 (11): 871–9. doi:10.1093/protein/15.11.871. PMID 12538906.
  11. Hegyi H, and Gerstein M. (1999). "The relationship between protein structure and function: a comprehensive survey with application to the yeast genome". J Mol Biol. 288 (1): 147–64. doi:10.1006/jmbi.1999.2661. PMID 10329133.
  12. Banner, D.W.; Bloomer, AC; Petsko, GA; Phillips, DC; Pogson, CI; Wilson, IA; Corran, PH; Furth, AJ; et al. (1975). "Structure of chicken muscle triose phosphate isomerase determined crystallographically at 2.5 angstrom resolution using amino acid sequence data". Nature. 255 (5510): 609–614. Bibcode:1975Natur.255..609B. doi:10.1038/255609a0. PMID 1134550.
  13. 1 2 Orengo CA, Michie AD, Jones S, Jones DT, Swindells MB, Thornton JM.; Michie; Jones; Jones; Swindells; Thornton (1997). "CATH--a hierarchic classification of protein domain structures". Structure. 5 (8): 1093–108. doi:10.1016/S0969-2126(97)00260-8. PMID 9309224.
  14. Copley, R. R. & Bork, P (2000). "Homology among (betaalpha)(8) barrels: implications for the evolution of metabolic pathways". J Mol Biol. 303 (4): 627–641. doi:10.1006/jmbi.2000.4152. PMID 11054297.
  15. Lesk, A. M.; Brändén, C. I.; Chothia, C (1989). "Structural principles of alpha/beta barrel proteins: The packing of the interior of the sheet". Proteins: Structure, Function, and Genetics. 5 (2): 139–48. doi:10.1002/prot.340050208. PMID 2664768.
  16. 1 2 Jones S, Stewart M, Michie A, Swindells MB, Orengo C, Thornton JM.; Stewart; Michie; Swindells; Orengo; Thornton (1998). "Domain assignment for protein structures using a consensus approach: characterization and analysis". Protein Sci. 7 (2): 233–42. doi:10.1002/pro.5560070202. PMC 2143930Freely accessible. PMID 9521098.
  17. 1 2 Holm L, Sander C.; Sander (1994). "Parser for protein folding units". Proteins. 19 (3): 256–68. doi:10.1002/prot.340190309. PMID 7937738.
  18. Ghélis C, Yon JM.; Yon (1979). "[Conformational coupling between structural units. A decisive step in the functional structure formation]". C R Seances Acad Sci D. 289 (2): 197–9. PMID 117925.
  19. Ostermeier M, Benkovic SJ.; Benkovic (2000). "Evolution of protein function by domain swapping". Adv Protein Chem. Advances in Protein Chemistry. 55: 29–77. doi:10.1016/s0065-3233(01)55002-0. ISBN 9780120342556. PMID 11050932.
  20. 1 2 ANFINSEN CB, HABER E, SELA M, WHITE FH Jr.; Haber; Sela; White (1961). "The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain". Proc Natl Acad Sci USA. 47 (9): 1309–14. Bibcode:1961PNAS...47.1309A. doi:10.1073/pnas.47.9.1309. PMC 223141Freely accessible. PMID 13683522.
  21. Cordes, M. H., Davidson, A. R., and Sauer, R. T (1996). "Sequence space, folding and protein design". Curr Opin Struct Biol. 6 (1): 3–10. doi:10.1016/S0959-440X(96)80088-1. PMID 8696970.
  22. Zhou, Y., Vitkup, D., and Karplus, M (1999). "Native proteins are surface-molten solids: application of the Lindemann criterion for the solid versus liquid state". J Mol Biol. 285 (4): 1371–1375. doi:10.1006/jmbi.1998.2374. PMID 9917381.
  23. Levitt, M.; Chothia, C. (1976). "Structural patterns in globular proteins". Nature. 261 (5561): 552–558. Bibcode:1976Natur.261..552L. doi:10.1038/261552a0. PMID 934293.
  24. Hutchinson EG, Thornton JM.; Thornton (1993). "The Greek key motif: extraction, classification and analysis". Protein Eng. 6 (3): 233–45. doi:10.1093/protein/6.3.233. PMID 8506258.
  25. Savageau MA. (1986). "Proteins of Escherichia coli come in sizes that are multiples of 14 kDa: domain concepts and evolutionary implications". Proc Natl Acad Sci USA. 83 (5): 1198–202. Bibcode:1986PNAS...83.1198S. doi:10.1073/pnas.83.5.1198. PMC 323042Freely accessible. PMID 3513170.
  26. 1 2 3 Islam SA, Luo J, Sternberg MJ.; Luo; Sternberg (1995). "Identification and analysis of domains in proteins". Protein Eng. 8 (6): 513–25. doi:10.1093/protein/8.6.513. PMID 8532675.
  27. Wheelan, S. J. and Marchler-Bauer, A. and Bryant, S. H. (2000). "Domain size distributions can predict domain boundaries". Bioinformatics. 16 (7): 613–618. doi:10.1093/bioinformatics/16.7.613. PMID 11038331.
  28. 1 2 Garel, J. (1992). "Folding of large proteins: Multidomain and multisubunit proteins". In Creighton, T. Protein Folding (First ed.). New York: W.H. Freeman and Company. pp. 405–454. ISBN 0-7167-7027-X.
  29. Bennett MJ, Schlunegger MP, Eisenberg D.; Schlunegger; Eisenberg (1995). "3D domain swapping: a mechanism for oligomer assembly". Protein Sci. 4 (12): 2455–68. doi:10.1002/pro.5560041202. PMC 2143041Freely accessible. PMID 8580836.
  30. Heringa J, Taylor WR.; Taylor (1997). "Three-dimensional domain duplication, swapping and stealing". Curr Opin Struct Biol. 7 (3): 416–21. doi:10.1016/S0959-440X(97)80060-7. PMID 9204285.
  31. Jacob F. (1977). "Evolution and tinkering". Science. 196 (4295): 1161–6. Bibcode:1977Sci...196.1161J. doi:10.1126/science.860134. PMID 860134.
  32. Ren, S.; Yang, G.; He, Y.; Wang, Y.; Li, Y.; Chen, Z. (2008). "The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains". BMC Genomics. 9: 452. doi:10.1186/1471-2164-9-452. PMC 2576256Freely accessible. PMID 18828911.
  33. Campbell ID, Downing AK.; Downing (1994). "Building protein structure and function from modular units". Trends Biotechnol. 12 (5): 168–72. doi:10.1016/0167-7799(94)90078-7. PMID 7764899.
  35. Orengo CA, Jones DT, Thornton JM.; Jones; Thornton (1994). "Protein superfamilies and domain superfolds". Nature. 372 (6507): 631–4. Bibcode:1994Natur.372..631O. doi:10.1038/372631a0. PMID 7990952.
  36. Apic, G., Gough, J., and Teichmann, S. A (2001). "Domain combinations in archaeal, eubacterial and eukaryotic proteomes". J Mol Biol. 310 (2): 311–325. doi:10.1006/jmbi.2001.4776. PMID 11428892.
  37. Davidson JN, Chen KC, Jamison RS, Musmanno LA, Kern CB.; Chen; Jamison; Musmanno; Kern (1993). "The evolutionary history of the first three enzymes in pyrimidine biosynthesis". BioEssays. 15 (3): 157–64. doi:10.1002/bies.950150303. PMID 8098212.
  38. Henikoff S, Greene EA, Pietrokovski S, Bork P, Attwood TK, Hood L.; Greene; Pietrokovski; Bork; Attwood; Hood (1997). "Gene families: the taxonomy of protein paralogs and chimeras". Science. 278 (5338): 609–14. Bibcode:1997Sci...278..609H. doi:10.1126/science.278.5338.609. PMID 9381171.
  39. Bork, P. & Doolittle, R. F (1992). "Proposed acquisition of an animal protein domain by bacteria2". Proc Natl Acad Sci USA. 89 (19): 8990–8994. Bibcode:1992PNAS...89.8990B. doi:10.1073/pnas.89.19.8990. PMC 50050Freely accessible. PMID 1409594.
  40. Heringa J. (1998). "Detection of internal repeats: how common are they?". Curr Opin Struct Biol. 8 (3): 338–45. doi:10.1016/S0959-440X(98)80068-7. PMID 9666330.
  41. Politou, A. S., Gautel, M., Improta, S., Vangelista, L., and Pastore, A (1996). "The elastic I-band region of titin is assembled in a 'modular' fashion by weakly interacting Ig-like domains". J Mol Biol. 255 (4): 604–616. doi:10.1006/jmbi.1996.0050. PMID 8568900.
  42. 1 2 McLachlan, A. D (1979). "Gene duplications in the structural evolution of chymotrypsin". J Mol Biol. 128 (1): 49–79. doi:10.1016/0022-2836(79)90308-5. PMID 430571.
  43. Moore JD, Endow SA.; Endow (1996). "Kinesin proteins: a phylum of motors for microtubule-based motility". BioEssays. 18 (3): 207–19. doi:10.1002/bies.950180308. PMID 8867735.
  44. Russell, R. B (1994). "Domain insertion". Protein Eng. 7 (12): 1407–1410. doi:10.1093/protein/7.12.1407. PMID 7716150.
  45. Haynie DT, Xue B (2015). "Superdomain in the protein structure hierarchy: the case of PTP-C2". Protein Science. 24: 874–82. doi:10.1002/pro.2664. PMC 4420535Freely accessible. PMID 25694109.
  46. Levinthal, C. (1968). "Are there pathways for protein folding?" (PDF). J Chim Phys. 65: 44–45.
  47. Dill KA. (1999). "Polymer principles and protein folding". Protein Sci. 8 (6): 1166–80. doi:10.1110/ps.8.6.1166. PMC 2144345Freely accessible. PMID 10386867.
  48. Leopold PE, Montal M, Onuchic JN.; Montal; Onuchic (1992). "Protein folding funnels: a kinetic approach to the sequence-structure relationship". Proc Natl Acad Sci USA. 89 (18): 8721–5. Bibcode:1992PNAS...89.8721L. doi:10.1073/pnas.89.18.8721. PMC 49992Freely accessible. PMID 1528885.
  49. Dill KA, Chan HS.; Chan (1997). "From Levinthal to pathways to funnels". Nat Struct Biol. 4 (1): 10–9. doi:10.1038/nsb0197-10. PMID 8989315.
  50. White SH, Jacobs RE.; Jacobs (1990). "Statistical distribution of hydrophobic residues along the length of protein chains. Implications for protein folding and evolution". Biophys J. 57 (4): 911–21. Bibcode:1990BpJ....57..911W. doi:10.1016/S0006-3495(90)82611-4. PMC 1280792Freely accessible. PMID 2188687.
  51. George RA, Heringa J.; Heringa (2002). "SnapDRAGON: a method to delineate protein structural domains from sequence data". J Mol Biol. 316 (3): 839–51. doi:10.1006/jmbi.2001.5387. PMID 11866536.
  52. George RA, Lin K, Heringa J.; Lin; Heringa (2005). "Scooby-domain: prediction of globular domains in protein sequence". Nucleic Acids Res. 33 (Web Server issue): W160–3. doi:10.1093/nar/gki381. PMC 1160142Freely accessible. PMID 15980446.
  53. Desmadril, M. & Yon, J. M (1981). "Existence of intermediates in the refolding of T4 lysozyme at pH 7.4". Biochem Biophys Res Commun. 101 (2): 563–569. doi:10.1016/0006-291X(81)91296-1. PMID 7306096.
  54. Teale JM, Benjamin DC.; Benjamin (1977). "Antibody as immunological probe for studying refolding of bovine serum albumin. Refolding within each domain". J Biol Chem. 252 (13): 4521–6. PMID 873903.
  55. Creighton, T. E. (1983). Proteins: Structures and molecular properties. Freeman, New York. Second edition.
  56. 1 2 Sowdhamini R, Blundell TL.; Blundell (1995). "An automatic method involving cluster analysis of secondary structures for the identification of domains in proteins". Protein Sci. 4 (3): 506–20. doi:10.1002/pro.5560040317. PMC 2143076Freely accessible. PMID 7795532.
  57. Swindells, M. B (1995). "A procedure for detecting structural domains in proteins". Protein Sci. 4 (1): 103–112. doi:10.1002/pro.5560040113. PMC 2142966Freely accessible. PMID 7773168.
  58. Janin, J. & Wodak, S. J (1983). "Structural domains in proteins and their role in the dynamics of protein function". Prog Biophys Mol Biol. 42 (1): 21–78. doi:10.1016/0079-6107(83)90003-2. PMID 6353481.
  59. Tsai CJ, Nussinov R.; Nussinov (1997). "Hydrophobic folding units derived from dissimilar monomer structures and their interactions". Protein Sci. 6 (1): 24–42. doi:10.1002/pro.5560060104. PMC 2143523Freely accessible. PMID 9007974.
  60. 1 2 Crippen, G. M (1978). "The tree structural organisation of proteins". J Mol Biol. 126 (3): 315–332. doi:10.1016/0022-2836(78)90043-8. PMID 745231.
  61. Rossmann MG, Moras D, Olsen KW.; Moras; Olsen (1974). "Chemical and biological evolution of nucleotide-binding protein". Nature. 250 (463): 194–9. Bibcode:1974Natur.250..194R. doi:10.1038/250194a0. PMID 4368490.
  62. Rose GD. (1979). "Hierarchic organization of domains in globular proteins". J Mol Biol. 134 (3): 447–70. doi:10.1016/0022-2836(79)90363-2. PMID 537072.
  63. 1 2 Go N, Taketomi H.; Taketomi (1978). "Respective roles of short- and long-range interactions in protein folding". Proc Natl Acad Sci USA. 75 (2): 559–63. Bibcode:1978PNAS...75..559G. doi:10.1073/pnas.75.2.559. PMC 411294Freely accessible. PMID 273218.
  64. 1 2 Holm L, Sander C.; Sander (1997). "Dali/FSSP classification of three-dimensional protein folds". Nucleic Acids Res. 25 (1): 231–4. doi:10.1093/nar/25.1.231. PMC 146389Freely accessible. PMID 9016542.
  65. 1 2 Siddiqui AS, Barton GJ.; Barton (1995). "Continuous and discontinuous domains: an algorithm for the automatic generation of reliable protein domain definitions". Protein Sci. 4 (5): 872–84. doi:10.1002/pro.5560040507. PMC 2143117Freely accessible. PMID 7663343.
  66. Zehfus, M. H (1997). "Identification of compact, hydrophobically stabilized domains and modules containing multiple peptide chains". Protein Sci. 6 (6): 1210–1219. doi:10.1002/pro.5560060609. PMC 2143719Freely accessible. PMID 9194181.
  67. Taylor WR. (1999). "Protein structural domain identification". Protein Eng. 12 (3): 203–16. doi:10.1093/protein/12.3.203. PMID 10235621.
  68. Wodak, S. J. & Janin, J (1981). "Location of structural domains in protein". Biochemistry. 20 (23): 6544–6552. doi:10.1021/bi00526a005. PMID 7306523.
  69. Rashin, 1985
  70. Zehfus MH, Rose GD.; Rose (1986). "Compact units in proteins". Biochemistry. 25 (19): 5759–65. doi:10.1021/bi00367a062. PMID 3778881.
  71. 1 2 Potestio, R., Pontiggia, F. and Micheletti, C. (2009). "Coarse-grained description of protein internal dynamics: an optimal strategy for decomposing proteins in rigid subunits.". Biophysical Journal. 96 (12): 4993–5002. Bibcode:2009BpJ....96.4993P. doi:10.1016/j.bpj.2009.03.051. PMC 2712024Freely accessible. PMID 19527659.
  72. 1 2 Aleksiev, T., Potestio, R., Pontiggia, F., Cozzini, S. and Micheletti, C. (2009). "PiSQRD: a web server for decomposing proteins into quasi-rigid dynamical domains.". Bioinformatics. 25 (20): 2743–4. doi:10.1093/bioinformatics/btp512. PMID 19696046.
  73. Micheletti, C., Carloni, P. and Maritan, A. Accurate and efficient description of protein vibrational dynamics: comparing molecular dynamics and gaussian models, Proteins, 55, 635, 2004.
  74. Barclay A (2003). "Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules". Semin Immunol. 15 (4): 215–23. doi:10.1016/S1044-5323(03)00047-2. PMID 14690046.
  75. Bateman A, Coggill P, Finn RD; Coggill; Finn (October 2010). "DUFs: families in search of function". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 (Pt 10): 1148–52. doi:10.1107/S1744309110001685. PMC 2954198Freely accessible. PMID 20944204.

Key papers

External links

Structural domain databases

Sequence domain databases

Functional domain databases

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