Dimerization and ligand binding
Fanelli et al (2011).
In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site (i.e, a site other than the protein's active site).
Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors.
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| Source: google image, 2014 |
G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors constitute a large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses.
In humans, there are four types of adenosine receptors. Each is encoded by a separate gene and has different functions, although with some overlap. Both A1 receptors and A2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A2A receptor also has broader anti-inflammatory effects throughout the body.
A2AR dimerization affects the communication networks intrinsic to the receptor fold in a way dependent on the dimer architecture.
G protein Coupled Receptors (GPCRs) are allosteric proteins whose functioning fundamentals are the communication between the two poles of the helix bundle.
The representation of GPCR structures as Networks of Interacting Amino Acids (NIAA) can be a meaningful way to decipher the impact of ligand and of dimerization oligomerization on the molecular communication intrinsic to the protein fold.
Dimerization and ligand binding effect the structure network of A2A adenosine receptor
It is known that dimerization is a byproduct of evolution rather than instantaneous phenomenon. On the other hand, ligand binding, in spite of the fact of being well defined by evolution itself, is a phenomenon that happens on the moment, it does not exist, unless the ligand is on the range of reaching. In essence, we have two phenomena in different timescales: seconds and decades.
Bioinformatics and mathematical modelling
Guidolin et al (2011).
"A fundamental consequence of the view describing GPCRs as interacting structures, with the likely formation at the plasma membrane of receptor aggregates of multiple receptors (Receptor Mosaics) is that it is no longer possible to describe signal transduction simply as the result of the binding of the chemical signal to its receptor, but rather as the result of a filtering/integration of chemical signals by the Receptor Mosaics (RMs) and membrane-associated proteins.“
"....integrative functions emerging from the complex behaviour of these RMs"
"The concept of intra-membrane receptor–receptor interactions (RRIs) between different types of GPCRs and evidence for their existence was introduced by Agnati and Fuxe in 1980/81 through analysis of the effects of neuropeptides on the binding characteristics of monoamine receptors in membrane preparations from discrete brain regions"
"the hypothesis of high-order GPCR oligomers implies the existence of specific interaction interfaces allowing the assembly of macromolecular complexes."
"Experimental research, significant efforts were spent in bioinformatics to provide suggestions on the protein regions potentially playing a role in dimerization/oligomerization".
A first important consequence of such an arrangement is that the decoding process becomes a branched process (bifurcations) already at the receptor level in the plasma membrane allowing the different activation of some of the possible intracellular molecular pathways.
A second theoretical consequence is that some engrams can be stored.
Allosteric perturbations involve a shift of a population of pre-existing conformations.
Allostery can occur without a change in shape but purely in dynamics.
All of these analyses only provide suggestions that should be confirmed by experimental data since these studies, in general, do not consider several variables such as the micro-environment where the GPCRs are localized.
G-protein-coupled receptor dynamics: dimerization and activation models compared with experiment
Taddese et al (2012).
GPCRs (G-protein-coupled receptors) are dynamic structures, as shown by their ability to dimerize, domain swap, oligomerize, activate G-proteins, and signal via arrestin.
This provides evidence that bivalent ligands may indeed interact with
two binding sites in two receptors.
The receptor–dimer cooperativity index
Casadó et al (2007).
Almost all existing models that explain heptahelical G-protein-coupled receptor (GPCR) operation
are based on the occurrence of monomeric receptor species.
However, an increasing number of studies show that many G-protein-coupled heptahelical
membrane receptors (HMR)
are expressed in the plasma membrane as dimers.
"HMR are a superfamily of receptors with enormous current and future therapeutic potential."
The main aim of any of those models was to
explain the behaviour of G protein-coupled receptors (GPCR).
The majority of the models devised for HMR comes from the noncooperative 3-state mechanism
proposed 50 years ago
to explain the behaviour of nicotinic acetylcholine receptors,
which are ligand-gated ion channels but not HMR
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| Some models for non-interactive receptors |
The model considers an orthosteric center
where the agonist binds and subsequently displaces the equilibrium towards the active state.
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| Some models for non-interactive receptors |
They may modify the value of the dissociation constant (KD) of the agonist but not the total amount of receptors (RTotal).
The G protein, acting as an allosteric modulator, modifies the agonist binding and/or affects the equilibrium between R and R*.
Since the allosteric modulator (in this case the G protein) does not compete with orthosteric compounds, maximum binding is not affected but KD is.
None of these models is however able to satisfactorily explain the binding characteristics of receptors displaying biphasic binding isotherms (e.g., nonlinear Scatchard plots), such as, profiles of agonist binding to the orthosteric center with Hill coefficients different from 1
Single-molecule imaging revealed dynamic GPCR dimerization
Kasai and Kusumi (2014).
"G-protein-coupled receptors (GPCRs) undergo dynamic equilibrium between monomers and dimers"
"Within one second, GPCRs typically undergo several cycles of monomer and homo-dimer formation with different partners."
"Many GPCR dimers reported in the literature might actually be artifacts due to overexpression, particularly in the case of the class-A GPCRs"
Papers
Diego Guidolin, Francisco Ciruela, Susanna Genedani, Michele Guescini, Cinzia Tortorella, Giovanna Albertin, Kjell Fuxe, Luigi Francesco Agnati. Bioinformatics and mathematical modelling in the study of receptor–receptor interactions and receptor oligomerization. Biochimica et Biophysica Acta 1808 (2011) 1267–1283.
Bruck Taddese, Lisa M. Simpson, Ian D. Wall, Frank E. Blaney, Nathan J. Kidley, Henry S.X. Clark, Richard E. Smith, Graham J.G. Upton, Paul R. Gouldson, George Psaroudakis, Robert P. Bywater and Christopher A. Reynolds, G-protein-coupled receptor dynamics: dimerization and activation models compared with experiment. Biochemical Society Transactions (2012) Volume 40, part 2.
Vincent Casadó, Antoni Cortés, Francisco Ciruela, Josefa Mallol, Sergi Ferré, Carmen Lluis, Enric I. Canela, Rafael Franco. Old and new ways to calculate the affinity of agonists and antagonists interacting with G-protein-coupled monomeric and dimeric receptors: The receptor–dimer cooperativity index. Pharmacology & Therapeutics 116 (2007) 343–354
Rinshi S Kasai and Akihiro Kusumi. Single-molecule imaging revealed dynamic GPCR dimerization. Current Opinion in Cell Biology 2014, 27:78–86.
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