Rationalization of the effects of mutations on peptide andprotein aggregation rates

Abstract

In order for any biological system to function effectively, it is essential to avoid the inherent tendency of proteins to aggregate and form potentially harmful deposits. In each of the various pathological conditions associated with protein deposition, such as Alzheimer's and Parkinson's diseases, a specific peptide or protein that is normally soluble is deposited as insoluble aggregates generally referred to as amyloid. It is clear that the aggregation process is generally initiated from partially or completely unfolded forms of the peptides and proteins associated with each disease. Here we show that the intrinsic effects of specific mutations on the rates of aggregation of unfolded polypeptide chains can be correlated to a remarkable extent with changes in simple physicochemical properties such as hydrophobicity, secondary structure propensity and charge. This approach allows the pathogenic effects of mutations associated with known familial forms of protein deposition diseases to be rationalized, and more generally enables prediction of the effects of mutations on the aggregation propensity of any polypeptide chain.

Quantitative approaches to defining normal and aberrant protein homeostasis

“…[35][36][37][38] (2) New ideas about protein aggregation, 10,28 including the finding that the ability to assemble into stable and highly organised structures (e.g. amyloid fibrils) is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but rather a property shared by most, if not all, proteins; (3) The discovery that specific aspects of protein behaviour, including their aggregation propensities 21,23,39,40 and the cellular toxicity associated with the aggregation process, 24,41 can be predicted with a remarkable degree of accuracy from the knowledge of their amino acid sequences; (4) The realisation that a wide variety of techniques originally devised for applications in nanotechnology can be used to probe the nature of protein aggregation and assembly and of the structures that emerge; 30,[42][43][44] and (5) The development of powerful approaches using model organisms for probing the origins and progression of misfolding diseases by linking concepts and principles emerging from in vitro studies to in vivo phenomena such as neurodegeneration. 24 An analysis of these results, which span across a wide range of subjects from neuroscience to nanoscience, reveals that the ability to keep proteins in their soluble form is absolutely central for the maintenance of cell homeostasis.…”

“…Considerable progress has been made in characterising the major physicochemical factors that promote the aggregation of polypeptide chains, and increasingly sophisticated computational approaches have been developed 21,23,39,40 that enable predictions to be made about a variety of features of the process of aggregation of peptides and proteins. On this basis a method of predicting ''aggregation propensity profiles'' has been established that enables the identification of regions with a high intrinsic propensity for aggregation, 21,23,39,40 providing a platform for further development of this approach.…”

“…On this basis a method of predicting ''aggregation propensity profiles'' has been established that enables the identification of regions with a high intrinsic propensity for aggregation, 21,23,39,40 providing a platform for further development of this approach.…”

“…Considerable attention has been devoted to exploring the nature and origin of such disorders from a structural viewpoint and to understanding the manner in which the balance between normal and aberrant conformational transitions can be perturbed. 20 Several studies have involved in vitro studies coupled with computer simulations, [20][21][22][23] and many others have been concerned with the goal of relating processes studied in atomic detail in the test tube to their quantitative effects in living systems. [24][25][26] Moreover, recent findings suggest that further developments in this area could have much more general relevance to understanding the way in which well-established physical and chemical principles can provide new insights into the apparent complexity of biology.…”

Unfolding, Aggregation, and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

“…This partially denatured, " molten globule" state provides an alternate environment that may stabilize " non-native" secondary structure elements along different regions of the sequence. At this stage, the specific sequence and physiochemical properties of the amino acids, such as hydrophobicity, secondary structure propensity and electrostatic charge, are very influential in determining aggregation of the protein strands, and subsequent fibril formation (25).…”