Nucleic Acids Research Advance Access originally published online on October 26, 2007
Nucleic Acids Research 2008 36(Database issue):D700-D706; doi:10.1093/nar/gkm907
Nucleic Acids Research, 2008, Vol. 36, Database issue D700-D706
© 2007 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.
The Molecule Pages database
Brian Saunders1,
Stephen Lyon1,
Matthew Day2,
Brenda Riley2,
Emily Chenette3 and
Shankar Subramaniam1,4,*
1San Diego Supercomputer Center San Diego, La Jolla, CA 92093, 2Nature Publishing Group, 25 First Street, Cambridge, MA 02141, USA, 3Nature Publishing Group, The Macmillan Building, 4 Crinan Street, London N1 9XW, UK and 4Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
*To whom correspondence should be addressed. Tel: +1 858 822 0986; Fax: +1 858 822 3752; Email: shankar{at}sdsc.edu
Received August 31, 2007. Revised October 4, 2007. Accepted October 5, 2007.
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ABSTRACT
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The UCSD-Nature Signaling Gateway Molecule Pages (
http://www.signaling-gateway.org/molecule)
provides essential information on more than 3800 mammalian proteins
involved in cellular signaling. The Molecule Pages contain expert-authored
and peer-reviewed information based on the published literature,
complemented by regularly updated information derived from public
data source references and sequence analysis. The expert-authored
data includes both a full-text review about the molecule, with
citations, and highly structured data for bioinformatics interrogation,
including information on protein interactions and states, transitions
between states and protein function. The expert-authored pages
are anonymously peer reviewed by the Nature Publishing Group.
The Molecule Pages data is present in an object-relational database
format and is freely accessible to the authors, the reviewers
and the public from a web browser that serves as a presentation
layer. The Molecule Pages are supported by several applications
that along with the database and the interfaces form a multi-tier
architecture. The Molecule Pages and the Signaling Gateway are
routinely accessed by a very large research community.
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INTRODUCTION
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The UCSD-Nature Signaling Gateway (
http://www.signaling-gateway.org)
is a collaboration between the University of California, San
Diego and the Nature Publishing Group (NPG), designed to facilitate
navigation of the complex world of research into cellular signaling.
The Signaling Gateway is made up of three components: the Molecule
Pages (described in this study), the Signaling Update and the
Data Center. The Signaling Update is published weekly by the
NPG to provide topical and timely information about progress
in signal transduction research. The Signaling Gateway was formerly
sponsored by the Alliance for Cellular Signaling (AfCS) (
1,
2),
which performed comprehensive experimental analyses of selected
signaling systems. The Data Center section of the web site contains
all the data generated by the AfCS during the period Signaling
Gateway was part of the AfCS.
The Signaling Gateway Molecule Pages (SGMP) database provides essential information on more than 3800 proteins involved in cellular signaling in mammals, with each protein having its own Molecule Page. Molecule Page information is presented in two categories: author-entered data and automated data. Author-entered data contain expert-authored and peer-reviewed information based on published literature, with both review style free text with citations, and highly structured data for bioinformatic interrogation. The information is linked to appropriate journal citations, and covers areas such as protein interactions and states, transitions between states and protein function. The automated data information is a collection of public bioinformatic data source links and sequence analysis results, derived from the sequence and data record used to define the Molecule Page. The SGMP base organism is Mus musculus (because of the mouse-centric focus of the AfCS), though much of the information in the SGMP is derived from homologous proteins in other species, such as Homo sapiens.
Once the author-entered information has gone through a peer review process, the Molecule Page is published. The published Molecule Pages are citable and to date NPG has published entries for 365 proteins, with nearly 130 submitted Molecule Pages currently in the review system, and 350 Molecule Pages in author preparation. New published Molecule Pages are promoted through the Signaling Update website pages, e-alerts and linkouts from NPG content.
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DATABASE CONTENT
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The SGMP is a complicated online annotation and publishing system,
containing three major subcomponents: (i) online pathway curation
(author-entered data); (ii) online peer review and (iii) public
repository data acquisition and display (automated data). The
peer review information and the pre-published author-entered
information for a given Molecule Page are only visible to the
author, selected reviewers and the editorial staff, and are
invisible to all other users. The automated data for each Molecule
Page is visible to all users.
Each Molecule Page is assigned a specific protein sequence, a name, a list of synonyms and a specific protein function category (based on ‘best fit’). That information is used to generate the properties of the sequence such as molecular weight, and all the automated data associated with the sequence. A combination of database links and computational methods are used to find the related database records and the parameters of computational matches (e.g. a domain region). This information is displayed in the ‘Protein Overview’ section of the Molecule Page, which is the landing page for unpublished Molecule Pages.
Author-entered data
To illustrate the depth of the author-entered data, we choose Adenylyl cyclase type 5 (SGMP ID A000001). Because this is a published Molecule Page, the user first arrives at the ‘Abstract’ section, which gives information on the author (Carmen W. Dessauer), gives a summary of the role of Adenylyl cyclase type 5, lists the names and synonyms provided by the author and the editors, indicates that A000001 molecule has 32 enzyme functions, exists in 33 states, has 96 transitions between these states, and shows a miniature version of the network map of these transitions. The ‘Full Text’ section contains a textual description—with published references—of protein function, regulation, interactions, subcellular localization, expression, phenotypes, splice variants and antibodies. The ‘States’ section lists each defined functional state, with links to a constituent list and a transition graph (if applicable) to indicate all the transitions that lead to the state. A protein state is defined by the principal proteins interactions with other protein partners, covalent modifications on all protein components, association with small molecule ligands and cellular location. The ‘Transitions’ section shows a list of the defined transitions, with a link to detailed information on each transition—with initial and final state information, the change that occurred in the transition, process information, other comments and citations (Figure 1). A transition is defined as a biological process that causes the conversion of a protein from one state to another. The ‘Network Map’ gives a graphical representation of all the states, and the transitions between them, defined by the author for A000001 (Figure 2). The ‘Functions’ section shows that A000001 acts as an enzyme, catalyzing the conversion of Mg-ATP to cyclic AMP and pyrophosphate. Each state that catalyzes the reaction is listed, with a link to the detailed state information, and a link to detailed function information with reaction information, comments and citations (Figure 3). The ‘Protein Classes’ section shows classes defined by the author to aid in data entry and display—a class is defined as a group of three or more proteins that behave identically in a particular state.
Automated data
The ‘Protein Records’ section displays all the sequence
database records related to particular Molecule Page. A specific
record, defined by an NCBI protein GI number (
3), is assigned
to the Molecule Page as a base sequence. All the other sequence
records listed in the same Entrez Gene (
4) record are displayed,
as well as any UniProt (
5) and Ensembl (
6) records that refer
to those sequence records. The records are grouped by their
specific sequence. The ‘Gene Info’ page displays
pertinent information related to the Molecule from the Entrez
Gene record, including any related Ensembl gene records or the
sequence records within it. The ‘Domains & Motifs’
(
Figure 4) section contains domain information Pfam (
7) and
Smart (
8), pattern/motif information from PRINTS (
9) and InterPRO
(
10) records related to the Molecule Page sequence. These records
are produced using a combination of database record references,
computational schemes [hmmpfam (
11) and FingerPRINTScan (
12)].
Matching sequence regions are given for the computational matches.
The ‘Interactions’ page displays matching interaction
database records from the BIND database and from the Entrez
Gene database, including BIND (
13), BioGRID (
14) and HPRD (
15)
interaction records. Interactions involving likely orthologs
of the Molecule Page base sequence are displayed, to provide
additional information. The ‘Orthologs’ section
shows genes in other select organisms that are likely orthologs
of the base gene. This list is constructed using a combination
of a species-specific Blast against the NCBI protein database,
and database analysis of HomoloGene (
16) and Ensembl homology
databases. The ‘Blast Data’ section contains a list
of the top Blast hits against the entire NCBI protein database.
The Protein ‘Structure’ section displays the PDB
(
17) records that are related to the Molecule Page, either through
a database reference to one of the related protein sequence
records, or by a sequence match with Blast.
In addition to all the hyperlinks to the relevant bioinformatic
databases, the SGMP base sequence also links directly to the
SDSC Biology Workbench (
http://workbench.sdsc.edu). The Biology
Workbench (
18) enables a user to carry out seamlessly a variety
of sequence analysis operations. The link is located on the
‘Protein Overview’ page.
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EDITORIAL PROCESS
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NPG and UCSD are assisted by a scientific Advisory Board and
an Editorial Board. The Advisory Board provides high-level guidance
and advice concerning the development of the Molecule Pages
database. The Editorial Board helps the editorial team with
several aspects of publishing Molecule Pages, such as identifying
relevant authors, reviewers and adjudication during peer-review.
NPG manages a rigorous editorial process to ensure that expert-authored Molecule Pages are accurate and complete, and that structured data is recorded in a consistent manner. Authors either apply to contribute and are selected by NPG editors, or are commissioned by editors. After an initial editorial evaluation of an author's submission, the Molecule Page undergoes anonymous peer-review by two or three experts in the relevant field. Following peer-review the author may be required to revise their submission in light of reviewer and editor comments. Following revision the Molecule Page is critically assessed and a decision to publish is made. The Molecule Page is copy edited before publication and a Digital Object Identifier (DOI) assigned upon publication.
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DATABASE IMPLEMENTATION
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The SGMP is a multi-tier Enterprise Java web application. The
database tier is an Oracle 10g database instance running on
a Sun server. The middle tier contains business and web components
and is deployed on an Oracle Components 4 Java (OC4J) application
server that also runs on a Sun server. The client tier consists
of a web browser running on the user's machine. The business
components consist of data access objects that encapsulate database
access for the web layer. The web layer consists of Java servlets
and server pages complying with the J2EE (Enterprise Java) 1.3
specifications. The compute and database servers are located
at the San Diego Supercomputer Center (SDSC). SDSC provides
hardware, network and system administrative support.
In addition to the web forms that the general public uses for viewing the data, there are specialized web forms for the authors, reviewers and editors to perform their tasks. A password-protected user access system controls access to the specialized forms and the unpublished data for a given Molecule Page, but the general public is able to access any published data and all automated data without having to register for an account. Registration to the Signaling Gateway is, and always will be, free.
The automated data is calculated monthly. Local copies of the constituent databases are stored in custom, relational forms on the Oracle system, with the computational methods being run on Sun systems. The results of the automated data are stored in the database tier, along with the archived results of automated analysis at the time of publication. Tab-delimited files relating the Molecule Pages to protein sequence database records (e.g. UniProt, Refseq, Genbank) and gene database records (Entrez Gene and Ensembl) are provided via anonymous ftp.
The data is accessed via a browse function, a simple search engine and an advanced search engine. The simple search engine allows users to query the database using the Molecule Page ID, gene symbols, protein names and synonyms. The advanced search engine allows users to ask complex questions, such as ‘show me all functional states involving Molecule A and Molecule B.’ The advanced search engine uses the Lucene library (http://lucene.apache.org/) from the Apache Software Foundation (http://www.apache.org/)—an open-source Java toolset.
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FUTURE DIRECTIONS
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A wiki will be added to the web site, allowing for open comments
on any given Molecule Page, as well as a living molecule summary
that does not require the rigorous process of a published Molecule
Page. Previously published Molecule Pages will be updated by
the authors, and released as subsequent versions. We plan on
adding exportable Molecule Page information, for published Molecule
Pages, in XML form, as well as standard exchange formats such
as BioPAX (
http://www.biopax.org/). We will continue to add
to the links provided in the automated data sections, addressing
areas such as gene expression and phosphorylation.
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ACKNOWLEDGEMENTS
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We would like to acknowledge National Institutes of Health Grant
[5 U54 GM62114-06], the National Institute of General Medical
Science glue grant, which supported the AfCS. We thank Dr Alfred
Gilman, the principle investigator of the AfCS project, as well
as the members of the AfCS research team, many of whom were
integral in the development and beta testing of the Molecule
Pages. Warren Hedley, Yuhong Ning and Ilango Vadivelu contributed
to the business and presentation tiers of the Molecule Page
application, and Joshua Li contributed to the Oracle database
tier.
Timo Hannay, the Publishing Director at Nature.com, was instrumental in the creating of the alliance with Nature Journal, and provides invaluable advice for the development and directions of the Signaling Gateway. Barbara Marte and Bernd Pulverer of Nature provide much needed advice on editorial decisions. Our editorial advisory board contains Pat Casey, Michael Berridge, Tony Hunter and Robin Irvine, and in addition we would like to acknowledge all our editorial board. The UCSD-Nature Signaling Gateway is funded by the National Institutes of Health Grant [1 R01 GM078005-01]. Funding to pay the Open Access publication charges for this article was provided by The National Institutes of Health Grant [1 R01 GM078005-01].
Conflict of interest statement. None declared.
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ABSTRACT
INTRODUCTION
