Requirements and ontology for a G protein-coupled receptor oligomerization knowledge base

Abstract

Background: G Protein-Coupled Receptors (GPCRs) are a large and diverse family of membrane proteins whose members participate in the regulation of most cellular and physiological processes and therefore represent key pharmacological targets. Although several bioinformatics resources support research on GPCRs, most of these have been designed based on the traditional assumption that monomeric GPCRs constitute the functional receptor unit. The increase in the frequency and number of reports about GPCR dimerization/oligomerization and the implication of oligomerization in receptor function makes necessary the ability to store and access information about GPCR dimers/oligomers electronically.

Results: We present here the requirements and ontology (the information scheme to describe oligomers and associated concepts and their relationships) for an information system that can manage the elements of information needed to describe comprehensively the phenomena of both homo- and hetero-oligomerization of GPCRs. The comprehensive information management scheme that we plan to use for the development of an intuitive and user-friendly GPCR-Oligomerization Knowledge Base (GPCR-OKB) is the result of a community dialog involving experimental and computational colleagues working on GPCRs.

Conclusion: Our long term goal is to disseminate to the scientific community organized, curated, and detailed information about GPCR dimerization/oligomerization and its related structural context. This information will be reported as close to the data as possible so the user can make his own judgment on the conclusions drawn for a particular study. The requirements and ontology described here will facilitate the development of future information systems for GPCR oligomers that contain both computational and experimental information about GPCR oligomerization. This information is freely accessible at http://www.gpcr-okb.org.

Figure 1

Traditional and current views of GPCR signaling. The traditional view of GPCR signaling assumed that monomeric receptors participated in ligand binding and signal transduction. The current view suggests that GPCRs may form homo- and/or hetero-oligomers, and that ligand(s) binding to one or more receptors may activate neighboring receptors in the oligomeric complex.

Figure 2

UML diagram of the Oligomer concept and related concepts. Each concept is shown as a box, and is named in the top section of the box. All attributes for each concept are listed in the middle section of the box. Arrows represent relationships between concepts, and open-ended arrows indicate "is a" relationships. The relationship of one concept to another is indicated by the text on each arrow. Arrows with [0..*] (zero or more) or [1..*] (one or more) indicate the number of instances of the concept at the end of the arrow that is associated with the concept at the beginning of the arrow. The Oligomer concept is central to the GPCR oligomerization ontology and all other concepts in the ontology relate to it either directly (e.g., Oligomer ''is described by'' IdentificationStudy) or indirectly (e.g., Oligomer ''is composed of'' one or more [1..*] Protein that ''belongs to'' Family).

Figure 3

UML diagram of modeling-related concepts. Structural models of Oligomers are represented in the GPCR oligomerization ontology by a MolecularStructure concept. Each MolecularStructure is created with an instance of MethodType, and may be analyzed by many computational methods (instances of Analysis). MethodType has two subclasses: IdentificationMethod, which is used to identify the oligomer, and CreationMethod, which is used to create the MolecularStructure. IdentificationMethod and CreationMethod can have many sub-concepts that describe the precise type of method. In this figure we show only a few examples of such concepts.

Figure 4

UML diagram of concepts related to oligomerization-induced phenotype changes. The GPCR oligomerization ontology focuses on changes in the phenotype that occur when GPCR protomers oligomerize. There are three types of phenotypic change that are described by the ontology: changes in internalization, changes in signaling, and differences in the ligand binding of the oligomer as compared to any of the constituent protomers. The effect that ligand(s) binding to one or more of the protomers in an oligomer may have on binding of ligands to other protomers, or on the change in signaling, is described by the CrossTalk concept. The Internalization concept is used to describe changes that different ligands have on the trafficking of the Oligomer to the cell membrane. Any information that is available about the mechanism of activation of the Oligomer is stored in the MechanismOfActivation concept. The PhysiologicalRelevance concept stores information about the Oligomer in vivo.

Figure 5

UML diagram of the oligomerization-induced cooperativity effects in HEK-293 cells co-expressing μ-opioid and δ-opioid receptors. The attribute bindingXTalk compiles any information related to changes in the affinity of the ligandUnderTest (DAMGO) in the presence of another ligand (e.g., TIPP Ψ, deltorphin II, SNC80, or DPDPE). Treatment of HEK-293 cells with the selective δ-opioid ligand TIPP Ψ results in increased binding of the μ-opioid agonist DAMGO (see CrossTalk1). Among the δ-opioid selective agonists SNC 80, DPDPE or deltorphin II, only the last leads to a significant increase in DAMGO's binding affinity (see CrossTalk2-4).