Multiple conformational selection and induced fit events take place in allosteric propagation

Abstract

The fact that we observe a single conformational selection event during binding does not necessarily mean that only a single conformational selection event takes place, even though this is the common assumption. Here we suggest that conformational selection takes place not once in a given binding/allosteric event, but at every step along the allosteric pathway. This view generalizes conformational selection and makes it applicable also to other allosteric events, such as post-translational modifications (PTMs) and photon absorption. Similar to binding, at each step along a propagation pathway, conformational selection is coupled with induced fit which optimizes the interactions. Thus, as in binding, the allosteric effects induced by PTMs and light relate not only to population shift; but to conformational selection as well. Conformational selection and population shift take place conjointly.

Keywords: Allosteric; Allostery; Binding; Conformational selection; Induced fit; Molecular recognition.

Fig. 1.

Schematic illustrations of binding by ‘lock and key’ (Panel A), ‘induced fit’ (Panel B) and ‘conformational selection’ models (Panel C). According to the ‘lock and key’ model (Panel A), binding takes place when there is an exact geometric fit between the ligand and receptor. The cross sign denotes the absence of binding when the shapes do not match. Thus, among the pool of protein molecules (each protein type shown in a different color) the ligand selects the one whose shape is complementary. According to the ‘induced fit’ model (Panel B) there is no exact fit between the ligand and receptor before binding (shown by the cross on the receptor whose shape is complementary to the ligand). The ligand binds a protein molecule, inducing changes in the protein shape to fit the ligand. In the ‘conformational selection’ model (Panel C), the ligand selects a conformer from a pool of conformers of the same protein, whose shape is complementary via the same lock and key criterion. The different conformations of the same receptor are in the same color (green). The figure is adapted from Fig. 3 in Allosteric conformational barcode direct signaling in the cell. Nussinov R, Ma B, Tsai CJ, Csermely, P. Structure, 2013, September issue [67], with permission.

Fig. 2.

A schematic illustration of the role of conformational selection in a binding event. Panel A emphasizes that conformational selection via a binding event is coupled with a population shift, which allosterically helps in guiding the next binding event. The free energy landscape illustrates that the relative stabilities of the conformers change following binding. In Panel B, a complex with four entities in a linear association is used here to illustrate three possible association pathways shaped by conformational selection events in a hierarchical process.

Fig. 3.

An illustration of the role played by allostery on diversified cellular pathways with signaling through a single G protein-coupled receptor (GPCR). Initially, the two main branching pathways divide through an allosteric conformational selection of distinct GPCR active states by various types of agonist binding. In the agonist (G protein-dependent) pathway, the activated GPCR either activates the heterotrimeric G proteins which then promote the consequent signaling of the second messenger such as cyclic AMP, or recruits the GPCR kinases (GRKs) to phosphorylate Ser/Thr in the cytoplasmic loops and tail of the GPCR which in turn enable the recruitment of β-arrestins to mediate receptor desensitization and internalization. In the biased agonist (arrestin-dependent) pathway, distinct active GPCR conformations activate different sets of GRKs to create distinct phosphorylation patterns (barcodes) on GPCR. It is the barcode [67,103 ] that imparts distinct conformations, which in turn recruit arrestins with diverse conformations (illustrated in different colors in the Figure) to mediate different signaling pathways such as the ERK1/2 activation. Recruitment can be either through orthosteric or allosteric interactions.