Biological activity and pathological implications of misfolded proteins

Abstract

The physiological metabolism of proteins guarantees that different cellular compartments contain the appropriate concentration of proteins to perform their biological functions and, after a variable period of wear and tear, mediates their natural catabolism. The equilibrium between protein synthesis and catabolism ensures an effective turnover, but hereditary or acquired abnormalities of protein structure can provoke a premature loss of biological function, an accelerated catabolism and diseases caused by the loss of an irreplaceable function. In certain proteins, abnormal structure and metabolism are associated with a strong tendency to self-aggregation into a polymeric fibrillar structure, and in these cases the disease is not principally caused by the loss of an irreplaceable function but by the action of this new biological entity. Amyloid fibrils are an apparently inert, insoluble, mainly extracellular protein polymer that kills the cell without tissue necrosis but by activation of the apoptotic mechanism. We analyzed the data reported so far on the structural and functional properties of four prototypic proteins with well-known biological functions (lysozyme, transthyretin, beta 2-microglobulin and apolipoprotein AI) that are able to create amyloid fibrils under certain conditions, with the perspective of evaluating whether the achievement of biological function favors or inhibits the process of fibril formation. Furthermore, studying the biological functions carried out by amyloid fibrils reveals new types of protein-protein interactions in the transmission of messages to cells and may provide new ideas for effective therapeutic strategies.

Structure-Activity Relations of Successful Pharmacologic Chaperones for Rescue of Naturally Occurring and Manufactured Mutants of the Gonadotropin-Releasing Hormone Receptor

“…Subsequently, the arresting observation was made ) that 11 of the 13 reported human mutants of the GnRHR that cause hypogonadotropic hypogonadism Leañ os-Miranda et al, 2002) could be rescued by this approach, as could many "manufactured" mutants (truncations, deletions, and Cys substitutions), suggesting the generality of this approach. Based on this and a similar observation for the V2 receptor (Morello et al, 2000), we proposed ) that this approach might be generally applicable to correcting diseases for which the etiology is misrouted or misfolded proteins, such as cystic fibrosis, nephrogenic diabetes insipidus, hypercholesterolemia, cataracts, Alzheimer's, retinitis pigmentosa, and others (Bellotti et al, 1999;Brooks, 1999;Radford and Dobson, 1999;Deen et al, 2000;Kopito and Ron, 2000;Morello et al, 2000;Sanders and Nagy, 2000;Dobson, 2001;Ellgaard and Helenius, 2001;Gregersen et al, 2001;Hammarstrom et al, 2001;Helenius, 2001;Sherman and Goldberg, 2001;Couzin, 2002;Hartl and Hayer-Hartl, 2002;Luque et al, 2002). Since rescue molecules need not bind mutants at ligand binding sites to serve as stabilizing scaffolding, it is likely that constituents of pharmaceutical archives that have failed agonist and antagonist screens may include unrecognized rescue molecules.…”

Amyloidogenesis of Natively Unfolded Proteins

“…The largest group of misfolding diseases, including numerous neurodegenerative disorders and the amyloidoses, originates from the conversion of specific proteins from their soluble functional states into stable, highly ordered, filamentous protein aggregates, known as amyloid fibrils, and from the deposition of these aggregated material in the variety of organs and tissues. In each of these pathological states, a specific protein or protein fragment changes from its natural soluble form into insoluble fibrils, which accumulate in a variety of organs and tissues [2][3][4][5][6][7][8].…”

“…In a rigid globular protein, such changes cannot take place due to the constraints of the tertiary structure. Therefore, it has been proposed that fibrillation of a globular protein requires the destabilization of its rigid native structure leading to a partial unfolding and the formation of a partially unfolded conformation [2][3][4][5][6][7][8][15][16][17][18]. As natively unfolded (intrinsically unstructured) proteins are devoid of ordered structure, the primary step of their fibrillogenesis requires the stabilization of a partially folded conformation, i.e.…”

Early Events in the Fibrillation of Monomeric Insulin

“…A number of human diseases are caused by the pathogenic deposition of proteins in the form of amyloid-like fibrils (1)(2)(3)(4)(5)(6)(7). Several non-pathogenic proteins and peptides also undergo amyloid like fibril formation on destabilization of their native state (7)(8)(9)(10).…”