Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders Michele Vendruscolo, Tuomas P.J. Knowles, and Christopher M. Dobson Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom Correspondence: [email protected] According to the “generic view” of protein aggregation, the ability to self-assemble into stable and highly organized structures such as 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 proteins. At the same time, through a wide variety of techniques, many of which were originally devised for applications in other disciplines, it has also been established that the maintenance of proteins in a soluble state is a fundamental aspect of protein homeostasis. Taken together, these advances offer a unified framework for understanding the molecular basis of protein aggregation and for the rational development of therapeutic strategies based on the biological and chemical regulation of protein solubility. irtually every complex biochemical process structures that results from protein folding, and Vtaking place in living cells depends on the which serve to bring key functional groups into ability of the molecules involved to self- close proximity, has enabled living systems to assemble into functional structures (Dobson develop an astonishing diversity and selectivity 2003; Robinson et al. 2007; Russel et al. 2009), in their underlying chemical processes by using and a sophisticated quality control system is a common set of just 20 basic molecular com- responsible for regulating the reactions leading ponents, the amino acids (Dobson 2003). Given to this organization within the cellular environ- the central importance of protein folding,it isnot ment (Dobson 2003; Balch et al. 2008; Hartl surprising that the failure of proteins to fold cor- and Hayer-Hartl 2009; Powers et al. 2009; Ven- rectly, or to remain correctly folded, is at the ori- druscolo and Dobson 2009). Proteins are the gin of a wide variety of pathological conditions, molecules that are essential for enabling, regulat- including late-onset diabetes, cystic fibrosis, and ing, and controlling almost all the tasks necessary Alzheimer’s and Parkinson’s diseases (Dobson to maintain such a balance. To function, the 2003; Chiti and Dobson 2006; Haass and Selkoe majorityof our proteins need to fold into specific 2007). In many of these disorders proteins self- three-dimensional structures following their assemble in an aberrant manner into large mo- biosynthesis in the ribosome (Hartl and Hayer- lecular aggregates, notably amyloid fibrils (Chiti Hartl 2002). The wide variety of highly specific and Dobson 2006;Ramirez-Alvarado etal. 2010). Editors: Richard I. Morimoto, Dennis Selkoe, and Jeff Kelly Additional Perspectives on Protein Homeostasis available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a010454 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a010454 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press M. Vendruscolo et al. PROTEIN FOLDING AND MISFOLDING interdisciplinary research environments that use wide ranges of advanced procedures, both ex- In the late 1990s, experimental data started to perimental and theoretical (Morimoto 2008; become available, suggesting that the amyloid Hartl and Hayer-Hartl 2009; Powers et al. state is not simply associated with a few dis- 2009). In our own group we initially used these ease-related proteins, but it is a “generic” state methods in the fields of biophysics and struc- accessible in principle to essentially all proteins tural biology (Dobson 2003; Jaroniec et al. (Guijarro et al. 1998; Dobson 1999). In addi- 2004; Carulla et al. 2005, 2009; Smith et al. tion, because the types of structural interactions 2006; Knowles et al. 2007a, 2009; Orte et al. within the amyloid state and the native state are 2008); they have now been extended into bio- similar, their thermodynamic stabilities are chemistry and cell biology (Chiti et al. 1999; likely to be comparable under many circum- Fandrich et al. 2001; de la Paz et al. 2002; stances (Dobson 2003; Knowles et al. 2007a). Dumoulin et al. 2003; Dedmon et al. 2005; On this assumption, there will be a competition Wright et al. 2005; Baglioni et al. 2006), and between these two states that results in normal the results have led to fundamentally new ideas or aberrant biological behavior depending on about the nature of protein structures, how they whether the native or the aggregated state is have evolved to be as they are, and why they are populated under given circumstances. More now increasingly associated with emerging dis- generally, the maintenance of the correct bal- eases in the modern world (Chiti and Dobson ance in the populations of different states of 2006). Most recently, these various ideas have proteins is of great significance, as even mar- been tested in living systems by using model ginal alterations in such populations can result organisms such as Caenorhabditis elegans in disease in the long term (Dobson 2003; Balch (Roodveldt et al. 2009) and Drosophila mela- et al. 2008; Geiler-Samerotte et al. 2011). nogaster (Luheshi et al. 2007, 2010). These Indeed, it has been recently shown that the limit developments, as well as many others (Balch to the “safe” concentration of proteins in living et al. 2008; Hartl and Hayer-Hartl 2009; Powers systems is reached when the stability of the alter- et al. 2009), have made it possible to begin to native aggregated state becomes comparable to relate in detail the mechanisms of protein fold- that of the native state (Tartaglia et al. 2007; ing and misfolding, uncovered from in vitro Powers et al. 2009). It is therefore of great studies, with the origins and progression in importance to complement the well-established vivo of the most common and debilitating characterization of the structure, folding, and neurodegenerative diseases. In addition to pro- stability of native states with a similar analysis moting a deeper understanding of these rapidly of the structure, assembly, and stability of other proliferating disorders, such an understanding states—ranging from unfolded and partially will form a novel and robust basis for new folded species, including natively unfolded approaches to their prevention and therapy states, to aggregated species such as amyloid (Dobson 2004). fibrils (Fig. 1). One particularly effective ap- proach has been to incorporate data from PROTEIN AGGREGATION AND DISEASE nuclear magnetic resonance (NMR) spectro- scopy and other experiments in molecular Strategies based on biophysical approaches are dynamics simulations (Vendruscolo et al. 2001; likely to play an increasingly important role in Lindorff-Larsen et al. 2005; Vendruscolo and the study of protein homeostasis (Fig. 1). This Dobson 2005; Gianni et al. 2010). view has been prompted by the realization, There is an increasing interest in develop- made through initial observations of protein ing an understanding of how proteins fold aggregation by us and by others, that the ki- correctly to generate normal biological func- netics of this phenomenon are of critical impor- tion, or misfold to generate disease. To achieve tance but have great complexity (Harper and this objective, it is necessary to create highly Lansbury 1997; Kelly 1998; Serio et al. 2000; 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a010454 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Protein Solubility and Protein Homeostasis Disordered Disordered aggregate aggregate Oligomer Fiber Native Synthesis Unfolded Intermediate Crystal Disordered Degraded Prefibrillar aggregate fragments species Amyloid fibril Figure 1. Protein behavior in the cell. Protein homeostasis refers to the ability of cells to generate and regulate the levels of their constituent proteins in terms of conformations, interactions, concentrations, and cellular localization. Failure to fold, or to remain correctly folded, can result in misfolding and aggregation, which are processes associated with a wide range of human disorders, including Alzheimer’s and Parkinson’s diseases (Dobson 2003). Dobson 2003; Haass and Selkoe 2007; Knowles process of aggregation, and thus be in a position et al. 2009). The experience we gained in our to carry out a quantitative analysis of the cellular studies of protein folding, in which biophys- and organismal responses associated with this ical and theoretical methods have together phenomenon. been crucial to establish a firm understanding A particularly clear example of the great of this process (Wolynes et al. 1995; Dobson potential of this approach has been the study et al. 1998), suggested that to make advances of the microscopic processes underlying pro- in the field of protein aggregation, similar strat- tein aggregation. Here, the analytical solution egies were needed. It is now important to bring of the equations describing the time evolution together methods of biochemistry and cell of the fibrillar assemblies identified the three biology with those of physical chemistry and principal events that play a key role in deter- biophysics,