these include : prosite ( 2 ) , which uses regular expressions and profiles , prints ( 3 ) , which uses position specific scoring matrix - based ( pssm - based ) fingerprints , prodom ( 4 ) , which uses automatic sequence clustering , and pfam ( 5 ) , smart ( 6 ) , tigrfams ( 7 ) , pirsf ( 8) , superfamily ( 9 ) , gene3d ( 10 ) and panther ( 11 ) , all of which use hidden markov models ( hmms ) .
protein signatures from these databases that describe the same family or domain , in terms of sequence positions and protein coverage are integrated into single interpro entries , to which are added annotation and cross - references .
annotation includes an abstract , name , short name and go terms ( 12 ) ( where applicable ) .
all matches of the protein signatures contributed by member databases against the uniprot knowledgbase ( uniprotkb ) ( 13 ) are calculated using the interproscan software ( 14 ) , which integrates the search algorithms from the member databases into a single package .
the interpro data are available for searching and retrieval via a web interface at , and for download by anonymous ftp .
coverage of protein sequences and amino acid residues for each member database not all the methods are integrated into interpro entries , e.g. for panther , but interpro provides matches to them in the match xml file .
two new member databases , panther and gene3d , have joined the interpro consortium and their hmms are being integrated .
in addition , new database cross - references to clustr ( 15 ) and pfam clans ( 5 ) have been included , and entries link to the intact molecular interaction database ( 16 ) where manually curated examples of domain  domain interactions are available .
proteins with 3d structures modelled by modbase ( 17 ) and swiss - model ( 18 ) have links to the structure predictions from the match graphical views .
these links complement the experimentally determined structures in the protein data bank ( pdb ) .
the web interface has been extended for more advanced searching capabilities , and a web service is now available , providing programmatic access to interproscan .
in addition to uniprotkb , interpro now provides matches to all proteins in the uniprot archive , uniparc , and these are currently available in xml format on the ftp site .
the match xml files are also indexed in srs to allow users to query the data within the srs interface . the new features of interpro are described in more detail below .
panther ( ) ( 11 ) hmms define protein families and subfamilies modelled on the divergence of specific functions within the families , which permits more accurate association with function based on ontology terms and pathways , as well as inference of amino acids important for functional specificity .
panther currently has high coverage of all families that contain at least one metazoan protein , including homologous proteins from all taxa .
consequently , coverage is very high for proteins found in animals and less so for other groups , such as plants , fungi and bacteria .
the addition of panther hmms to interpro is facilitating more fine - grained annotation of functionally and evolutionarily related subfamilies .
gene3d ( ) ( 10 ) is a library of hmms that represent all proteins of known structure .
the seed alignments for the models are derived from the proteins found within the homologous superfamily ( h - level ) classification level in cath , which groups together domains that are thought to share a common ancestor .
gene3d models are being integrated to complement the superfamily models that are based on scop superfamilies . to further extend the publications section of interpro entries ,
this field lists any publications provided by the member databases for the methods associated with each interpro entry , which are not directly referenced in the interpro abstract .
additionally , a maximum of five references per entry are taken from the pdb when one or more of the proteins in the entry has had its structure determined .
these references provide the user with additional publications to visit to find out more about the proteins in the entry , and also provide interpro curators with a list of references to consult when updating abstracts .
database links field has been extended to include new links to clustr and pfam clans .
table 2 lists the databases cross - referenced in interpro and the number of entries containing these links .
clustr ( ) ( 15 ) is a database containing protein clusters from more than 368 organisms with completely sequenced genomes .
interpro entries are linked to protein clusters only where at least 70% of the clustr members occur in the interpro entry .
links to pfam clan pages are now available in the database links field where applicable .
a clan contains two or more pfam families that have arisen from a single evolutionary origin , based on evidence from structure , function , profile  profile comparisons and whether the sequences are matched by more than one hmm .
clans were introduced to resolve the issue of pfam hmms overlapping on a sequence , as this is forbidden in the pfam database .
the link from interpro entries to clans provides a popup display of the pfam clan name and all pfam clan members with their corresponding interpro accession numbers .
these interpro entries will not necessarily be related to each other through parent / child or contains / found in relationships .
number of interpro entries with cross - references to the databases interpro provides links to links to intact ( ) ( 16 ) , the molecular interaction database , have been incorporated into interpro , providing manually curated examples of domain  domain interactions .
intact incorporates protein  protein interaction data derived from the literature and direct submissions , and provides a query interface and modules to analyze the data .
links from interpro to intact are provided at the level of individual uniprotkb accessions , and are restricted to 20 randomly chosen examples .
there are currently 135 interpro entries with links to 1180 intact entries , involving 400 proteins .
this number is likely to remain low , compared to the total number of interactions in intact , as these links are based on well curated domain interactions , rather than every protein  protein interaction .
new positional links are available for uniprotkb proteins to modbase ( ) ( 17 ) and swiss - model ( ) ( 18 ) .
modbase is a database of 3d protein models calculated by comparative modelling using modpipe , an automated modelling pipeline relying on programs , such as psi - blast and modeller .
modbase matches to protein sequences are shown in the detailed graphical view as yellow and white striped bars .
swiss - model is a repository of annotated 3d protein structure models from the uniprotkb sequence database , and provides a protein structure homology modelling server .
matches to protein sequences are shown in the detailed graphical view as red and white striped bars .
these cross - references , as well the other links to more than 30 different databases , increase the value of interpro with respect to its interoperability and integration with other data sources .
protein matches in interpro are pre - calculated using the interproscan software ( 14 ) .
interproscan is a tool that combines different protein signature recognition methods of the interpro member databases into one resource , and provides the corresponding interpro accession numbers and go annotation in the results .
interproscan can be used via a web interface or email server , which allows searching of a sequence against interpro , or it can be installed and run locally for bulk searches . a new development has been the establishment of a web service for running single or multiple sequences through interproscan . more information about the web service and example clients in perl and java for accessing the service is available from .
this service provides programmatic access to the tool for users who want to run bulk searches or use interproscan as part of a pipeline . over the past two years
previously , interpro matches were available only for uniprotkb proteins , but now interpro provides additional matches to alternative splice products and uniparc proteins . matches to splice variant sequences associated with uniprotkb accession numbers can be accessed through the  protein with splice variants link from the matches field , and are available through the compact and detailed displays .
the matches for the master sequence are shown at the top with the splice variant matches below them , so it is easy to identify where matches differ between isoforms .
the splice variant sequences originate from uniprotkb , and of the 25 927 splice variants available , 24 268 have hits to a total of 3483 interpro entries .
the uniprot archive ( uniparc ) is a repository of all protein sequences , with each unique sequence stored once .
these sequences are then cross - referenced to the relevant databases , e.g. uniprotkb , and include data submitted from metagenomics projects .
this repository contains 7.5 million protein sequences , including uniprotkb proteins , and therefore the calculation of interpro matches is slow .
these calculations are ongoing , and the data provided incorporates the most up - to - date matches available at that point in time . currently , there are just over 50 million interpro matches to uniparc proteins .
uniparc matches are not yet visible in interpro entries , but are available in xml format from the ftp site and are searchable in srs .
an additional match xml file , match_complete.xml , is provided with each release , and contains uniprotkb sequence matches for all member database signatures , including those that have not yet been integrated into interpro .
this is to ensure that the public has access to all protein signature matches that have been calculated .
all protein matches are updated on each major interpro release ( approximately every 3 months ) .
the web interface has been extended to provide additional searching options . from the text search page ( )
one can retrieve matches for a uniprotkb accession number by pasting the accession number in the search box and selecting  find protein matches. this returns the matches in a combination of formats .
the protein match views can also be selected in the matches section of an interpro entry , which provides options for displaying the matches in different tabular or graphical views . from any of these views
, the user can then select a set of proteins by uniprotkb accession number(s ) or interpro accession , and can refine the set to show splice variants or proteins with known structure or both .
tax id. once the protein set has been defined , the user can select the output display format from 
table , and can specify the order of proteins in the display by uniprotkb accession or identifier .
in addition to links to complete match lists , each interpro entry page contains a taxonomy wheel showing the taxonomic range of proteins matching the entry .
clickable. clicking on a particular lineage returns only the protein matches for the selected taxonomy . in this view , the species are sorted and displayed alphabetically and the lineage is shown at the top .
the numbers on the phylogeny show the number of proteins associated with each taxonomic group that match the entry .
panther ( ) ( 11 ) hmms define protein families and subfamilies modelled on the divergence of specific functions within the families , which permits more accurate association with function based on ontology terms and pathways , as well as inference of amino acids important for functional specificity .
panther currently has high coverage of all families that contain at least one metazoan protein , including homologous proteins from all taxa .
consequently , coverage is very high for proteins found in animals and less so for other groups , such as plants , fungi and bacteria .
the addition of panther hmms to interpro is facilitating more fine - grained annotation of functionally and evolutionarily related subfamilies .
gene3d ( ) ( 10 ) is a library of hmms that represent all proteins of known structure .
the seed alignments for the models are derived from the proteins found within the homologous superfamily ( h - level ) classification level in cath , which groups together domains that are thought to share a common ancestor .
gene3d models are being integrated to complement the superfamily models that are based on scop superfamilies . to further extend the publications section of interpro entries ,
this field lists any publications provided by the member databases for the methods associated with each interpro entry , which are not directly referenced in the interpro abstract .
additionally , a maximum of five references per entry are taken from the pdb when one or more of the proteins in the entry has had its structure determined .
these references provide the user with additional publications to visit to find out more about the proteins in the entry , and also provide interpro curators with a list of references to consult when updating abstracts .
database links field has been extended to include new links to clustr and pfam clans .
table 2 lists the databases cross - referenced in interpro and the number of entries containing these links .
clustr ( ) ( 15 ) is a database containing protein clusters from more than 368 organisms with completely sequenced genomes .
interpro entries are linked to protein clusters only where at least 70% of the clustr members occur in the interpro entry .
links to pfam clan pages are now available in the database links field where applicable .
a clan contains two or more pfam families that have arisen from a single evolutionary origin , based on evidence from structure , function , profile  profile comparisons and whether the sequences are matched by more than one hmm .
clans were introduced to resolve the issue of pfam hmms overlapping on a sequence , as this is forbidden in the pfam database .
the link from interpro entries to clans provides a popup display of the pfam clan name and all pfam clan members with their corresponding interpro accession numbers .
these interpro entries will not necessarily be related to each other through parent / child or contains / found in relationships .
number of interpro entries with cross - references to the databases interpro provides links to links to intact ( ) ( 16 ) , the molecular interaction database , have been incorporated into interpro , providing manually curated examples of domain  domain interactions .
intact incorporates protein  protein interaction data derived from the literature and direct submissions , and provides a query interface and modules to analyze the data .
links from interpro to intact are provided at the level of individual uniprotkb accessions , and are restricted to 20 randomly chosen examples .
there are currently 135 interpro entries with links to 1180 intact entries , involving 400 proteins .
this number is likely to remain low , compared to the total number of interactions in intact , as these links are based on well curated domain interactions , rather than every protein  protein interaction .
new positional links are available for uniprotkb proteins to modbase ( ) ( 17 ) and swiss - model ( ) ( 18 ) .
modbase is a database of 3d protein models calculated by comparative modelling using modpipe , an automated modelling pipeline relying on programs , such as psi - blast and modeller .
modbase matches to protein sequences are shown in the detailed graphical view as yellow and white striped bars .
swiss - model is a repository of annotated 3d protein structure models from the uniprotkb sequence database , and provides a protein structure homology modelling server .
matches to protein sequences are shown in the detailed graphical view as red and white striped bars .
these cross - references , as well the other links to more than 30 different databases , increase the value of interpro with respect to its interoperability and integration with other data sources .
protein matches in interpro are pre - calculated using the interproscan software ( 14 ) .
interproscan is a tool that combines different protein signature recognition methods of the interpro member databases into one resource , and provides the corresponding interpro accession numbers and go annotation in the results .
interproscan can be used via a web interface or email server , which allows searching of a sequence against interpro , or it can be installed and run locally for bulk searches . a new development has been the establishment of a web service for running single or multiple sequences through interproscan . more information about the web service and example clients in perl and java for accessing the service is available from .
this service provides programmatic access to the tool for users who want to run bulk searches or use interproscan as part of a pipeline . over the past two years
previously , interpro matches were available only for uniprotkb proteins , but now interpro provides additional matches to alternative splice products and uniparc proteins . matches to splice variant sequences associated with uniprotkb accession numbers can be accessed through the  protein with splice variants link from the matches field , and are available through the compact and detailed displays .
the matches for the master sequence are shown at the top with the splice variant matches below them , so it is easy to identify where matches differ between isoforms .
the splice variant sequences originate from uniprotkb , and of the 25 927 splice variants available , 24 268 have hits to a total of 3483 interpro entries .
the uniprot archive ( uniparc ) is a repository of all protein sequences , with each unique sequence stored once .
these sequences are then cross - referenced to the relevant databases , e.g. uniprotkb , and include data submitted from metagenomics projects .
this repository contains 7.5 million protein sequences , including uniprotkb proteins , and therefore the calculation of interpro matches is slow .
these calculations are ongoing , and the data provided incorporates the most up - to - date matches available at that point in time . currently , there are just over 50 million interpro matches to uniparc proteins .
uniparc matches are not yet visible in interpro entries , but are available in xml format from the ftp site and are searchable in srs .
an additional match xml file , match_complete.xml , is provided with each release , and contains uniprotkb sequence matches for all member database signatures , including those that have not yet been integrated into interpro .
this is to ensure that the public has access to all protein signature matches that have been calculated .
all protein matches are updated on each major interpro release ( approximately every 3 months ) .
the web interface has been extended to provide additional searching options . from the text search page ( )
one can retrieve matches for a uniprotkb accession number by pasting the accession number in the search box and selecting  find protein matches. this returns the matches in a combination of formats .
the protein match views can also be selected in the matches section of an interpro entry , which provides options for displaying the matches in different tabular or graphical views . from any of these views
, the user can then select a set of proteins by uniprotkb accession number(s ) or interpro accession , and can refine the set to show splice variants or proteins with known structure or both .
tax id. once the protein set has been defined , the user can select the output display format from 
table , and can specify the order of proteins in the display by uniprotkb accession or identifier .
in addition to links to complete match lists , each interpro entry page contains a taxonomy wheel showing the taxonomic range of proteins matching the entry .
clickable. clicking on a particular lineage returns only the protein matches for the selected taxonomy .
in this view , the species are sorted and displayed alphabetically and the lineage is shown at the top .
the numbers on the phylogeny show the number of proteins associated with each taxonomic group that match the entry .
interpro now integrates protein signatures from 10 different member databases , and links > 20 additional resources , including uniprotkb , structural data and specialized protein family databases .
it has proven its usefulness in the functional characterization of proteins , and is used by genome annotation projects ( 1922 ) and individual researchers worldwide . in the last year , the interpro website received 3 million hits per month from up to 35 000 unique hosts . through the mapping of interpro entries to go terms , interpro contributes the majority of annotations of proteins to go terms .
approximately 68% of all uniprotkb proteins are annotated with go terms from a combination of manual annotation and the use of mappings , such as interpro2go , swiss - prot keyword2go , etc .
interpro2go alone provides go annotations for 61% of uniprotkb proteins , thus accounting for a significant proportion of the total number of annotations currently available .
these go mappings are also available via interproscan , which facilitates go annotation to query proteins .
the current release of interpro contains more than 13 000 entries , with its signatures covering over 78% of uniprotkb proteins .
the integration of new protein signatures from the existing and new member databases will continue to increase the coverage , as well as the depth , of interpro .
future plans include the provision of protein match views for uniparc matches , facilitating the searching and browsing of interpro entries by function , and the provision of data for unintegrated protein signatures via the interpro web interface .
integration of signatures into interpro entries and subsequent annotation of the entries is done manually and is thus of high - quality , but is time - consuming . in order to make the signatures awaiting integration available to the public via the web interface
, new entries will be created automatically for the unintegrated signatures and will be searchable by their member database accession numbers .
the protein matches will be available in the same format as match views from interpro entries so that the user can see how the new signature relates to existing entries .
these new features will increase the usefulness of this already popular high - quality resource .
 interpro is an integrated resource for protein families , domains and functional sites , which integrates the following protein signature databases : prosite , prints , prodom , pfam , smart , tigrfams , pirsf , superfamily , gene3d and panther . 
 the latter two new member databases have been integrated since the last publication in this journal . 
 there have been several new developments in interpro , including an additional reading field , new database links , extensions to the web interface and additional match xml files . 
 interpro has always provided matches to uniprotkb proteins on the website and in the match xml file on the ftp site . 
 additional matches to proteins in uniparc ( uniprot archive ) are now available for download in the new match xml files only . 
 the latest interpro release ( 13.0 ) contains more than 13 000 entries , covering over 78% of all proteins in uniprotkb . 
 the database is available for text- and sequence - based searches via a webserver ( ) , and for download by anonymous ftp ( ) . 
 the interproscan search tool is now also available via a web service at . 
INTRODUCTION
NEW FEATURES OF INTERPRO
Annotation
Protein matches
Web interface
DISCUSSION