Role of Cooperativity in Protein Folding and Protein Mosaic Assemblage Relevance for Protein Conformational Diseases

Abstract

Biological systems are organized in intricate and highly structured networks with hierarchies and multiple scales. Cells can be considered as "meso-scale level" systems placed between the "macro-scale level" (systems of cellular networks) and the "micro-scale level" (systems of molecular networks). In fact, cells represent complex biochemical machineries made by networks of molecules connected by biochemical reactions. Thus, the brain should be studied as a system of "networks of networks". Recently, the existence of a Global Molecular Network (GMN) enmeshing the entire CNS was proposed. This proposal is based on the evidence that the extra-cellular matrix is a dynamic molecular structure capable of storing and releasing signals and of interacting with receptors and proteins on the cell membranes. Proteins have a special role in molecular networks since they can be assembled into high-order molecular complexes, which have been defined as Protein Mosaics (PM). Protein monomers in a PM (the "tesserae" of the mosaic) can interact via classical and non-classical cooperativity behaviour involving allosteric interactions. In the present paper, new features of allostery and cooperativity for protein folding, assemblage and topological features of PM will be discussed. Against this background, alterations in PM via allosteric modulations and non-classical cooperativity mechanisms may lead to protein aggregates like beta amyloid fibrils. Such aggregates cause pathological changes in the GMN structure and function leading to neurodegenerative diseases such as Alzheimer's disease. Thus, a novel view of the so called Protein Conformational Diseases (PCD) is proposed.

Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes

“…It is of substantial interest that available experimental investigations are, in general, supporting this prediction (Ciruela et al, 2004;Guo et al, 2008;Borroto-Escuela et al, 2010a). A significant consequence of the possible availability of multiple interaction interfaces is the possibility that the assemblage of the receptor molecules to form an oligomer could occur in a number of different geometrical arrangements (see Agnati et al, 2007bAgnati et al, , 2010dGuidolin et al, 2011). The upper panels show the tertiary structure of the interacting partners (D1R is shown in yellow; D2R, in cyan).…”

“…In particular, modulation of the intracellular molecular networks following the GPCR cross-talk at the plasma membrane level (i.e. the RRI) provides a strong support for RRI and can be investigated by means of ad hoc biochemical experiments (Agnati et al, , 2007b(Agnati et al, , 2008aFuxe et al, 2005Fuxe et al, , 2007a); 4. Corecognition that can be demonstrated by means of bivalent ligands capable of binding at the same time both partners in a pair of interacting receptors (Bhushan et al, 2004;Daniels et al, 2005;Hiller et al, 2013;Yekkirala et al, 2013).…”

“…According to the recent views (see Kenakin and Miller, 2010;Nussinov, 2013;Nussinov and Tsai, 2013), proteins subject to allosteric communication can be monomers or components of large, hetero-oligomeric complexes and allosteric behavior can be even displayed by single domains within a protein (see also Agnati et al, 2007bAgnati et al, , 2008b. Since allostery involves the propagation of signals between distant sites in a protein structure (Changeux and Edelstein, 2005), many experimental studies and theoretical models suggest that there is a network of physically interconnected and/or thermodynamically linked residues forming channels along which signals are communicated between binding sites (Goodey and Benkovic, 2008).…”

“…the available interaction interfaces) but also the microenvironment surrounding the interacting partners (i.e. the energy landscape; Frauenfelder et al, 1991), and can deeply influence the functional behavior of the RM (Agnati et al, 2007b). …”

Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia

“…This integrative process can involve cooperative allosteric interactions when receptor subtypes that recognize the same ligand are involved (Agnati et al 2007b, 2008; Fuxe et al 2007a, 2008). In addition, allosteric modulators that act at allosteric modulatory sites of one receptor may also participate in this integrative process of heterodimer and receptor mosaic signaling (Agnati et al 2006, 2007a; Fuxe et al 2007a; Milligan and Smith 2007). The latter has been elegantly illustrated through works on homocysteine (Agnati et al 2006, 2007b).…”