the standard sequence - to - structure - to - function paradigm for proteins assumes that each protein first folds into a three - dimensional ( 3d ) structure and that the resulting structure enables function via the lock and key ( 1 ) or the induced fit ( 2 ) models . enzymes and their functions , which were traditionally the focus of studies in biochemistry , provided the basis for the lock and key and induced fit models ; hence , as expected these models generally and perhaps universally explain enzymatic function . one reflection of the intimate relationship between protein structure and catalytic function is the relatively higher coverage of enzymes in the protein data bank ( pdb ) as compared with other protein types ( 3 ) . non - catalytic protein functions relating to signaling , regulation and control , such as protein  protein interactions , protein  dna interactions , protein  rna interactions , post - translational modifications and linker activities to name a few , are increasingly being studied . many of these non - catalytic functions have been suggested to depend on , or have been experimentally demonstrated to depend on , proteins that lack fixed 3d structure , with interesting publications on this topic dating up to 70 years ago ( 48 ) . functional proteins that lack the relatively fixed structure of enzymes and other globular proteins have been called  rheomormorphic ( 9 ) ,  natively unfolded ( 10 ) ,  intrinsically unstructured ( 11 ) and  natively or intrinsically disordered ( 12 ) , among other terms . these proteins or protein regions exist as interconverting , dynamic ensembles of structures instead of folding into a single structure and many of their signaling or regulatory functions depend on their highly flexible nature . conformational flexibility facilitates a number of post - translational modifications , such as phosphorylation ( 13 ) and ubiquitination ( 1416 ) for example , possibly because similar sequence segments in different proteins can use this flexibility to conform to the active sites of the modifying enzymes . many protein - binding interactions important for signaling and regulation involve modular binding domains that often associate with rather short linear motifs ( 1721 ) . in many cases , these interactions involve disorder - to - order transitions for at least one of the partners . such complex formation by coupled folding and binding ( 22 ) provides an important mechanism for achieving both high specificity and low affinity ( 8) , which is an ideal combination for signaling and regulation . not only can individual disordered proteins and regions bind to multiple partners ( 46,23 ) , but also multiple disordered sequences can each adapt to fit one partner ( 24 ) . these partnering abilities of disordered proteins suggest their importance and common usage in protein interaction and signaling networks . some biological functions involve the flexibility itself , one important example being the ball and chain model for inactivation of voltage - gated ion channels ( 7 ) . often the flexibility of disordered regions provides a linker function to enable structured ( or unstructured ) functional domains to move relative to each other , which can lead to enhanced affinity . the experimental data describing intrinsically disordered proteins ( idps ) are growing rapidly due in part to the increasing interest in signaling , regulation and control . the rapidly increasing number of idp examples has generated the need for a publicly accessible repository . to facilitate efficient management and annotation of idp information , the database of disordered proteins ( disprot ) , disprot contained 460 idps and 1103 disordered regions , encompassing 35 functional categories  all based on published experimental data . intrinsically disordered regions and proteins carry out a number of vital functions in the living cell . a new structure  function paradigm that extends the aforementioned sequence - to - structure - to - function model by including disorder as a type of structure provides the basis for describing the functions that depend on disorder ( 11 ) . the  protein trinity hypothesis suggests that functional proteins can exist in one of three conformational states : the solid - like ordered state ( globular proteins ) , the liquid - like collapsed disordered state ( molten globule ) and the gas - like extended disordered state ( 25 ) . one more extended disordered conformation , the pre - molten globule state , was added to complete the  the protein quartet model ( 26 ) . the pre - molten globule contains specific regions that transiently form regular secondary structure while extended disorder lacks a significant amount of such regions and behaves more like a typical random coil . because the set of natively unfolded proteins probably forms a continuum ranging from little or no transient secondary structure to significant amounts of transient secondary structure but still without the compactness of the molten globule , it is uncertain whether the unfolded realm ought to remain as one category or be partitioned into two separate regions as suggested above . a difficulty with the partitioning is that it is unclear how to carry out this separation in a consistent manner . so given this uncertainty , function is then proposed to arise from any of these three ( trinity model ) or four ( quartet model ) states , or from transitions between them . currently , seven idp - related high - level functional classifications have been proposed and are included in disprot ( table 1 ) . these are chaperone , entropic chain , metal sponge , modification site , molecular assembly , molecular recognition effectors and molecular recognition scavengers . more specific function annotations , referred to here as functional subclasses , are also provided ( table 1 ) . only a few of the currently identified 35 functional subclasses attributed to idps are included in table 1 . as additional biological processes and functions are continuously identified as being dependent upon protein intrinsic disorder , we anticipate that functional classes and subclasses will be expanded upon over time . indeed , a recent bioinformatics study suggested that additional functions associated with protein disorder are evident in the literature ( see discussion ) . mining this new source of information will add to the idp functional classifications listed in disprot . examples of idp - related functional classes and subclasses the first column contains one of each of the high - level functional classes currently included in disprot . information in the remaining columns includes illustrative details for exemplary annotated proteins from the database with disordered regions that perform the indicated functions . regions may be annotated with multiple subclasses ( this is not reflected in the table ) . disprot provides users with a number of tools to carry out a variety of biological and computational analyses . some of these tools are as follows : disordered region sequence download , homologous protein sequence retrieval , functional narratives , graphical ordered and disordered region maps , isoform display , author - verified entries and a comprehensive bibliography for disordered proteins . from every protein entry page ( figure 1 ) , the sequence of the protein and disordered region(s ) homologues included in disprot obtained using the cd - hit clustering program with a 50% identity threshold , are also accessible via links . a manually annotated description of the protein and its functional role(s ) is provided in the functional narrative section . information on the protein family , cellular localization , or relation to cancer or any other disease is provided in the narrative . when a protein includes both ordered and disordered regions and when the ordered segment(s ) are in the pdb , the relevant pdb links are included . the protein and region map provides a visual representation of the location of the ordered and disordered regions in the context of the entire protein . author - verified protein entries are proteins in which the author(s ) of the referenced papers have reviewed and verified all disorder information available for that entry . at the time of this writing ( a ) protein display for dp000039 , non - histone chromosomal protein hmg-17 , and ( b ) bibliography query page . a searchable bibliography ( figure 1b ) that includes all the papers referenced by disprot , together with papers that have cited several key references on disordered proteins and some other papers found by keyword searches . although not displayed , abstract text is included in keyword searches in order to increase the usefulness of this collection . in addition , a link to the pubmed abstract is provided for every applicable paper . as of now , the total number of papers in the bibliography is 2289 . the number of papers published per year in this field growing rapidly as evident in figure 2 . the number of papers tallied by year referencing protein disorder that are included in the searchable bibliography of disprot . an additional feature of disprot related to individual protein entries that is not illustrated in figure 1a is that isoforms included in disprot ( produced primarily through alternative splicing ) are annotated as a sub - entry to the original protein . for example , information about isoform 1 of calcineurin , dp00092 , is coded in dp00092_a001 . since alternatively spliced segments of pre - mrna were recently shown to code for regions of intrinsic disorder much more frequently than they code for regions of 3d structure ( 27 ) , although the data in disprot are based on experimental data , predictors of protein disorder have been found to be useful for the analysis of relationships among primary amino acid sequence , structure and function of proteins ( 28,29 ) . this list is updated as new predictors become available . through display and tabulation of known disorder information of individual proteins combined with relationships among isoforms and similar proteins , disprot can supply useful examples for crystallographers and structural biologists as an aid to solving the structures of target proteins that contain unstructured regions . disorder can typically be characterized by x - ray crystallography , nmr spectroscopy , cd spectroscopy ( both far and near uv ) and protease sensitivity in addition to several other less frequently used experimental techniques . a comprehensive list of all detection methods currently used to characterize idps and the descriptions of these techniques can be found using convenient links provided in the database . each protein entry includes the method(s ) used for disorder characterization as well as the specific experimental conditions . clicking on a detection method link brings up a list of all proteins in the database that have been characterized using that particular method . disprot is supported by an apache web server with the web interface implemented using php and javascript . disprot is available to the public and can be accessed at . simplified idef1x representation of the disprot database structure . boxes with round edges represent tables with at least one foreign key . dashed lines with an oval at one end and a cross at the other represent mandatory relationships ( not null foreign keys ) , plane lines with an oval at one end and a cross at the other represent identifying relationship ( foreign keys , possibly null , for which the field names in the tables are identical ) , dashed lines with an oval at both ends represent non - identifying optional relationships ( foreign keys , possibly null , for which the field names are not identical ) . it is also possible to query the database using amino acid sequence , keywords , protein name , organism name or accession numbers from uniprot , swissprot , ncbi and other databases . query sequences are searched , using rps - blast , against a database containing the profiles of all the proteins in the current release . sequence homologues within disprot are found using the cd - hit-2d program with a 50% identity threshold . in addition , the complete disprot database is available for download in the fasta and xml format ( ) . disprot is the central repository for structure  function annotations associated with protein intrinsic disorder . these users are involved in many branches of protein science and are from a variety of different organization types , including academic , industry and government . the nearly 450 papers published in 2005 is about twice the number published in 2004 , and the number of papers in 2006 , although the year is not complete as of this writing , shows clear evidence of a continued rapid rise ( figure 2 ) . because inconsistent nomenclature is used to describe these proteins , the bibliography in disprot is very useful to researchers in this rapidly growing field . the rapid growth of disorder - related publications argues for the importance of having an organized database such as disprot . researchers who study idps are encouraged to look over this bibliography and to send us the citations of papers that we have missed . our initial attempt to identify disorder - function relationships led to 28 specific functions that we grouped into four classes ( 12 ) . a different schema was proposed at about the same time that led to additional functions being added ( 30 ) . the 7 and 35 functional classes and subclasses , respectfully , in the current disprot came mostly from these prior publications , but with a number of additions that were discovered during the process of annotating proteins . a search of the pdb for short segments called molecular recognition features , morfs , was carried out . morfs undergo disorder - to - order transitions upon binding to their partners , which typically have globular structure . this search yielded 1261 morfs that were clustered into 372 sets on the basis of high - sequence identity among members of a given set ( 31 ) . many of these morfs have experimental data supporting disorder - to - order transitions upon binding . in addition , proteins that undergo disorder - to - order transitions upon complex formation are distinguishable from globular proteins that associate with one another . the disorder - based complexes have larger monomer surface areas and larger interaction surface areas as compared to interacting globular proteins ( 32 ) . all of the 372 morf - partner complexes exhibit these large surface areas for the monomers and interfaces ; furthermore , nearly all of the morfs have substantial prediction of disorder in their flanking regions as well . both these observations support the concept that these interactions involve disorder - to - order transitions of the morfs ( 31 ) . direct experimental evidence in support of this concept has been presented in the case of deacetylation ( 33 ) and phosphorylation sites , sh3 interaction motifs ( 34 ) and recognition elements of 14 - 3 - 3 proteins ( 24 ) , which all have been found in locally disordered regions of their parent proteins . the possible generality of this mode of protein  protein interactions has also been underlined by predicting the local structural preferences of interaction sites of idps ( 35 ) . another approach , based on sequence comparison rather than analysis of structures in pdb , has been used to systematically identify short , linear motifs that bind to protein partners ( 20,21,36 ) . these sequence - identified segments have been collected and are contained in the eukaryotic linear motif ( elm ) server ( ) ( 20 ) . many of the sequence - based elms and the structure - based morfs are simply different descriptions of the same protein segments , and in these cases the elms likely undergo coupled binding and folding upon association with their partners ( fuxreiter , tompa and simon , work in progress ) . the elms that have been experimentally verified to be unstructured in the absence of their partners and the elm - morf matches will be added to disprot with appropriate cross - references to the elm collection . we recently carried out a bioinformatics study to determine which swiss protein keywords were associated with the prediction of long disordered regions and which keywords were associated with the absence of such predictions . of 711 function - associated keywords for which there were enough protein examples in swiss protein to make statistical inferences , 302 keywords were strongly associated with the absence of disorder prediction and 262 were strongly associated with the prediction of disorder . manual literature searches provided numerous confirmatory examples for which laboratory experiments verified the direct involvement of disordered regions in carrying out the identified functions ( h. xie , s. vucetic , l.m . , we will focus our annotation efforts on finding papers that determine whether or not idps are directly responsible for carrying out the 262 functions that were indicated to be idp - associated . this bioinformatics - directed disprot expansion will enable us to rapidly increase the number of experimentally verified disordered protein  function relationships . by expanding the number of different functions associated with experimentally characterized idps , disprot will become increasingly more useful in the field of genome annotation . since intrinsically disordered regions often show high - sequence variability compared with structured regions in the same proteins , identifying functional homologues by sequence matching will be generally more difficult for idps than for structured proteins . we previously showed that disordered regions could be classified based on differences in sequence properties and these disordered regions with differing sequence properties showed differences in function . a major goal in concert with the expansion of disprot will be to refine the associations between different functions and different sequence properties , thus facilitating the use of disprot for function annotation . given the high frequency of idps and the large number of functions carried out by these proteins , future versions of disprot and the associated tools to be developed will become essential for complete function annotation of proteomes . another direction of the disprot future development will be the elaboration of tools for the idp sequence analyses . . the availability of blast - like analyses using scoring matrices associated with the idp - specific sequence features would enable sequence / function relationships amongst idps to be more accurately analyzed . although in its current configuration disprot contains links to known publicly available disorder predictors , a planned development is a disorder prediction service , in which results are obtained from multiple servers and compiled in one report ( i.e. a service resembling the predictprotein server ( 37,38 ) . rather than limiting users to the predictors we have developed , we hope to make an array of predictors available , which can then be used in combination for more detailed analysis as described recently ( 39 ) . another useful tool is the recently described disorder score versus sequence complexity plot ( 40 ) ; these plots appear to be extremely useful for comparing idps . in these ways
the database of protein disorder ( disprot ) links structure and function information for intrinsically disordered proteins ( idps ) . 
 intrinsically disordered proteins do not form a fixed three - dimensional structure under physiological conditions , either in their entireties or in segments or regions . 
 we define idp as a protein that contains at least one experimentally determined disordered region . 
 although lacking fixed structure , idps and regions carry out important biological functions , being typically involved in regulation , signaling and control . 
 such functions can involve high - specificity low - affinity interactions , the multiple binding of one protein to many partners and the multiple binding of many proteins to one partner . 
 these three features are all enabled and enhanced by protein intrinsic disorder . 
 one of the major hindrances in the study of idps has been the lack of organized information . 
 disprot was developed to enable idp research by collecting and organizing knowledge regarding the experimental characterization and the functional associations of idps . 
 in addition to being a unique source of biological information , disprot opens doors for a plethora of bioinformatics studies . 
 disprot is openly available at .