New developments in the InterPro database
Nicola J. Mulder1,*, Rolf Apweiler1, Teresa K. Attwood3, Amos Bairoch4,5,
Alex Bateman2, David Binns1, Peer Bork6, Virginie Buillard4, Lorenzo Cerutti4,
Richard Copley7, Emmanuel Courcelle8, Ujjwal Das1, Louise Daugherty1, Mark Dibley9,
Robert Finn2, Wolfgang Fleischmann1, Julian Gough10, Daniel Haft11, Nicolas Hulo4,
Sarah Hunter1, Daniel Kahn12, Alexander Kanapin1, Anish Kejariwal13, Alberto Labarga1,
Petra S. Langendijk-Genevaux4, David Lonsdale1, Rodrigo Lopez1, Ivica Letunic6,
Martin Madera14, John Maslen1, Craig McAnulla1, Jennifer McDowall1, Jaina Mistry2,
Alex Mitchell1,3, Anastasia N. Nikolskaya15, Sandra Orchard1, Christine Orengo9,
Robert Petryszak1, Jeremy D. Selengut11, Christian J. A. Sigrist4, Paul D. Thomas13,
Franck Valentin1, Derek Wilson14, Cathy H. Wu15and Corin Yeats9
1EMBL Outstation—European Bioinformatics Institute and
Genome Campus, Hinxton, Cambridge, UK,3Faculty of Life Sciences and School of Computer Science, University of
Manchester, Manchester, UK,4Swiss Institute for Bioinformatics, Geneva, Switzerland,5Department of Structural
Biology and Bioinformatics, University of Geneva, Switzerland,6Biocomputing Unit EMBL, Heidelberg, Germany,
7Wellcome Trust Centre for Human Genetics, Oxford, UK,8CNRS/INRA, Toulouse, France,9Biochemistry and
Molecular Biology Department, University College London, University of London, UK,10Genomic Sciences Centre,
RIKEN Yokohama Institute, Suehiro-cho, Tsurumi-ku, Yokohama, Japan,11The Institute for Genomic Research,
Rockville, MD, USA,12Laboratoire de Biome ´trie et Biologie Evolutive and INRIA HELIX Project, University Lyon 1,
France,13Evolutionary Systems Biology Group, SRI International, Menlo Park, CA, USA,14MRC Laboratory of
Molecular Biology, Cambridge, UK and15Protein Information Resource, Georgetown University Medical Center,
Washington, DC, USA
2Wellcome Trust Sanger Institute, Wellcome Trust
Received September 5, 2006; Revised and Accepted October 6, 2006
InterPro is an integrated resource for protein fami-
lies, 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, inclu-
ding 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
(http://www.ebi.ac.uk/interpro), and for download by
anonymous FTP (ftp://ftp.ebi.ac.uk/pub/databases/
interpro). The InterProScan search tool is now also
available via a web service at http://www.ebi.ac.uk/
InterPro (1) incorporates the major protein signature data-
bases into a single resource. 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). Table 1 shows the coverage of each of these member
*To whom correspondence should be addressed. Tel: +44 1223 494 602; Fax: +44 1223 494 468; Email: firstname.lastname@example.org
Julian Gough, Unite de Bioinformatique Structurale, Institut Pasteur, Paris, France
? 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acids Research, 2007, Vol. 35, Database issue
databases. 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). Cross-
references are provided to specialized databases and protein
structural information. 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 pack-
age. The matches are available for viewing in various for-
mats for each InterPro entry. The InterPro data are
available for searching and retrieval via a web interface at
http://www.ebi.ac.uk/interpro, and for download by anony-
mous FTP ftp://ftp.ebi.ac.uk/pub/databases/interpro.
InterPro is constantly being updated to keep up with the
changing face of Bioinformatics. Two new member data-
bases, 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 molecu-
lar interaction database (16) where manually curated
examples of domain–domain interactions are available. Pro-
teins 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.
NEW FEATURES OF INTERPRO
Two new member databases have been integrated into
InterPro, PANTHER and Gene3D. PANTHER (http://www.
pantherdb.org) (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 (http://cathwww.biochem.ucl.
ac.uk:8080/Gene3D/) (10) is a library of HMMs that repre-
sent 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 inte-
grated to complement the SUPERFAMILY models that are
based on SCOP superfamilies.
To further extend the publications section of InterPro
entries, we have introduced the ‘additional reading’ field.
This field lists any publications provided by the member data-
bases 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
The ‘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 (http://www.ebi.ac.uk/clustr)
(15) is a database containing protein clusters from more
than 368 organisms with completely sequenced genomes.
The clustering is based on pairwise comparisons between
the protein sequences. 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.
Table 1. Coverage of protein sequences and amino acid residues for each member database
Member databaseNumber of
methods in InterProa
Total number of
proteins hit by database
Total number of
Number of unique proteins
hit by databaseb
1 736 593
2 502 476
1 929 112
395 970 746
173 969 368
58 525 186
55 137 257
16 861 589
153 498 831
570 591 566
61 153 722
94 310 609
484 789 136
170 121 752
aNot all the methods are integrated into InterPro entries, e.g. for PANTHER, but InterPro provides matches to them in the match XML file.
bThis is the number of proteins hit by one database only.
Nucleic Acids Research, 2007, Vol. 35, Database issueD225
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 overlap-
ping on a sequence, as this is forbidden in the Pfam database.
Clan information is used in post-processing of matches to
remove these overlaps. 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 necessar-
ily be related to each other through parent/child or contains/
found in relationships.
Links to IntAct (http://www.ebi.ac.uk/intact/site/) (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 submis-
sions, 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, invol-
ving ?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 (http://modbase.compbio.ucsf.edu/modbase-
cgi-new/index.cgi) (17) and SWISS-MODEL (http://swiss
model.expasy.org/) (18). MODBASE is a database of 3D pro-
tein models calculated by comparative modelling using
ModPipe, an automated modelling pipeline relying on pro-
grams, 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 interoperabil-
ity 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 access-
ing the service is available from http://www.ebi.ac.uk/Tools/
webservices/WSInterProScan.html. 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, additional protein matches have
become available in InterPro. 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 associ-
ated 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 metage-
nomics 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 (http://www.
ebi.ac.uk/interpro/search.html) the user can search within
Table 2. Number of InterPro entries with cross-references to the databases
InterPro provides links to
Database Number of InterPro entries with links
D226 Nucleic Acids Research, 2007, Vol. 35, Database issue
InterPro entries or protein matches. 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 vari-
ants or proteins with known structure or both. Alternatively,
the user can filter the protein set by taxonomy using the ‘tax
ID’. Once the protein set has been defined, the user can select
the output display format from ‘compact’, ‘detailed’, ‘archi-
tectures’ or ‘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 taxo-
nomic range of proteins matching the entry. The numbers
on the wheel for each taxonomic group are now ‘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 annota-
tion projects (19–22) 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 annota-
tion to query proteins. The current release of InterPro
contains more than 13 000 entries, with its signatures cover-
ing 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.
The InterPro database will continue to develop and
increase its functionality. 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.
The authors would like to thank Dr Steffen Schulze-Kremer
and the HLRN staff for their continued and valuable
assistance. InterPro is funded in part by the MRC e-family
grant number G0100305. A large proportion of HMMER-
based calculations are performed on the IBMP690 Super-
computer at HLRN. Funding to pay the Open Access
publication charges for this article was provided by the
European Bioinformatics Institute.
Conflict of interest statement. None declared.
1. Mulder,N.J., Apweiler,R., Attwood,T.K., Bairoch,A., Bateman,A.,
Binns,D., Bradley,P., Bork,P., Bucher,P., Cerutti,L. et al. (2005)
InterPro, progress and status in 2005. Nucleic Acids Res., 33,
2. Hulo,N., Bairoch,A., Bulliard,V., Cerutti,L., De Castro,E.,
Langendijk-Genevaux,P.S., Pagni,M. and Sigrist,C.J.A. (2006) The
PROSITE database. Nucleic Acids Res., 34, D227–D230.
3. Attwood,T.K., Bradley,P., Flower,D.R., Gaulton,A., Maudling,N.,
Mitchell,A.L., Moulton,G., Nordle,A., Paine,K., Taylor,P. et al. (2003)
PRINTS and its automatic supplement, prePRINTS. Nucleic Acids
Res., 31, 400–402.
4. Bru,C., Courcelle,E., Carrere,S., Beausse,Y., Dalmar,S. and Kahn,D.
(2005) The ProDom database of protein domain families: more
emphasis on 3D. Nucleic Acids Res., 33, D212–D215.
5. Finn,R.D., Mistry,J., Schuster-Bockler,B., Griffiths-Jones,S.,
Hollich,V., Lassmann,T., Moxon,S., Marshall,M., Khanna,A.,
Durbin,R. et al. (2006) Pfam: clans, web tools and services. Nucleic
Acids Res., 34, D247–D251.
6. Letunic,I., Copley,R.R., Pils,B., Pinkert,S., Schultz,J. and Bork,P.
(2006) SMART 5: domains in the context of genomes and networks.
Nucleic Acids Res., 34, D257–D260.
7. Haft,D.H., Selengut,J.D. and White,O. (2003) The TIGRFAMs
database of protein families. Nucleic Acids Res., 31, 371–373.
8. Wu,C.H., Nikolskaya,A., Huang,H., Yeh,L.S., Natale,D.A.,
Vinayaka,C.R., Hu,Z.Z., Mazumder,R., Kumar,S., Kourtesis,P. et al.
(2004) PIRSF: family classification system at the Protein Information
Resource. Nucleic Acids Res., 32, D112–D114.
9. Gough,J., Karplus,K., Hughey,R. and Chothia,C. (2001) Assignment of
homology to genome sequences using a library of Hidden Markov
Models that represent all proteins of known structure. J. Mol. Biol.,
10. Yeats,C., Maibaum,M., Marsden,R., Dibley,M., Lee,D., Addou,S. and
Orengo,C.A. (2006) Gene3D: modelling protein structure, function and
evolution. Nucleic Acids Res., 34, D281–D284.
11. Mi,H., Lazareva-Ulitsky,B., Loo,R., Kejariwal,A., Vandergriff,J.,
Rabkin,S., Guo,N., Muruganujan,A., Doremieux,O., Campbell,M.J.
et al. (2005) The PANTHER database of protein families, subfamilies,
functions and pathways. Nucleic Acids Res., 33, D284–D288.
12. Harris,M.A., Clark,J., Ireland,A., Lomax,J., Ashburner,M., Foulger,R.,
Eilbeck,K., Lewis,S., Marshall,B., Mungall,C. et al. (2004) The Gene
Ontology (GO) database and informatics resource. Nucleic Acids Res.,
Nucleic Acids Research, 2007, Vol. 35, Database issueD227
13. Wu,C.H., Apweiler,R., Bairoch,A., Natale,D.A., Barker,W.C.,
Boeckmann,B., Ferro,S., Gasteiger,E., Huang,H., Lopez,R. et al.
(2006) The Universal Protein Resource (UniProt): an expanding
universe of protein information. Nucleic Acids Res., 34, D187–D191.
14. Quevillon,E., Silventoinen,V., Pillai,S., Harte,N., Mulder,N.,
Apweiler,R. and Lopez,R. (2005) InterProScan: protein domains
identifier. Nucleic Acids Res., 33, W116–W120.
15. Petryszak,P., Kretschmann,E., Wieser,D. and Apweiler,R. (2005) The
predictive power of the CluSTr database. Bioinformatics, 21,
16. Hermjakob,H., Montecchi-Palazzi,L., Lewington,C., Mudali,S.,
Kerrien,S., Orchard,S., Vingron,M., Roechert,B., Roepstorff,P.,
Valencia,A. et al. (2004) IntAct: an open source molecular interaction
database. Nucleic Acids Res., 32, D452–D455.
17. Pieper,U., Eswar,N., Braberg,H., Madhusudhan,M.S., Davis,F.,
Stuart,A.C., Mirkovic,N., Rossi,A., Marti-Renom,M.A., Fiser,A. et al.
(2004) MODBASE, a database of annotated comparative protein
structure models, and associated resources. Nucleic Acids Res., 32,
18. Kopp,J. and Schwede,T. (2006) The SWISS-MODEL Repository: new
features and functionalities. Nucleic Acids Res., 34, D315–D318.
19. The International Human Genome Consortium (2001) Initial
sequencing and analysis of the human genome. Nature, 409,
20. Kawaji,H., Schonbach,C., Matsuo,Y., Kawai,J., Okazaki,Y.,
Hayashizaki,Y. and Matsuda,H. (2002) Exploration of novel motifs
derived from mouse cDNA sequences. Genome Res., 12, 367–378.
21. Yu,J., Hu,S., Wang,J., Wong,G.K., Li,S., Liu,B., Deng,Y., Dai,L.,
Zhou,Y., Zhang,X. et al. (2002) A draft sequence of the rice genome
(Oryza sativa L. ssp. indica). Science, 296, 79–92.
22. Rubin,G.M., Yandell,M.D., Wortman,J.R., Gabor Miklos,G.L.,
Nelson,C.R., Hariharan,I.K., Fortini,M.E., LiP,W., Apweiler,R.,
Fleischmann,W. et al. (2000) Comparative genomics of the eukaryotes.
Science, 287, 2204–2215.
D228Nucleic Acids Research, 2007, Vol. 35, Database issue