The Origin of Allosteric Functional Modulation: Multiple Pre-existing Pathways

Abstract

While allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein.

Allosteric signal transmission in the nucleotide-binding domain of 70-kDa heat shock protein (Hsp70) molecular chaperones

“…Therefore, not only do perturbations in the nucleotide-binding site affect subdomain interfaces, but also a signal can propagate from subdomain interfaces to the nucleotide-binding site, and in so doing regulate nucleotide binding and ATPase activity. Our results are entirely consistent with a previous hypothesis that allosteric signal transduction occurs via a network of motions of protein modules (e.g., subdomains) (30,31). According to this model, residues at the interfaces between modules form an allosteric network between protein active sites.…”

Overlap between folding and functional energy landscapes for adenylate kinase conformational change

“…In good agreement with our model for catalysis (that is, rate-limiting dissociation of bound nucleotides), the M1 and M2 variants display ~40-fold decrease in catalytic efficiency compared with WT AK e . The fact that mutations redistribute already existing states is in agreement with arguments discussed previously 7 . On the basis of these arguments, we propose that local disordering of α6 and α7 is part of the reaction trajectory for closure of the ATP lid (Fig.…”

“…Moreover, many proteins undergo significant conformational changes on interaction with target proteins or small ligands 3,4 . In analogy to the energy landscape model of protein folding 5 , transitions between native conformational states in folded proteins are thought to be achieved through multiple pathways 6,7 . Qualitative descriptions of conformational changes can be inferred from analysis of the stable ground states.…”

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…The available IL-2 structures reveal no major differences beyond a handful of alternative side chain rotamers (notably His 16) in the IL-2Rb-binding region. In a more general sense, however, these discoveries raise the enticing possibility that other PPI domains possess hidden allosteric potential that can be exploited for drug discovery (del Sol et al 2009). …”

“…1). In some cases, hotspots contain regions of structural flexibility, allowing the same protein surface to bind multiple partners (DeLano et al 2000), or the PPI to allosterically alter protein function (Gold et al 2006;del Sol et al 2009). Finally, PPI affinity varies from the micromolar to the picomolar range, implying a wide range of interaction dynamics and perhaps a range of inherent binding energy of the protein surfaces.…”