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Protein Misfolding, Functional Amyloid, and Human Disease

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Protein Misfolding, Functional Amyloid, and Human Disease ANRV277-BI75-14 ARI 8 May 2006 20:57 Protein Misfolding, Functional Amyloid, and Human Disease Fabrizio Chiti1 and Christopher M. Dobson2 1Dipartimento di Scienze Biochimiche, Universita` degli Studi di Firenze, I-50134 Firenze, Italy; email: fabrizio.chiti@unifi.it 2Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom; email: [email protected] Annu. Rev. Biochem. Key Words 2006. 75:333–66 aggregation mechanism, Alzheimer, Parkinson, prion, protein The Annual Review of Biochemistry is online at aggregation biochem.annualreviews.org Abstract doi: 10.1146/ annurev.biochem.75.101304.123901 Peptides or proteins convert under some conditions from their sol- Copyright c 2006 by uble forms into highly ordered fibrillar aggregates. Such transitions Annual Reviews. All rights can give rise to pathological conditions ranging from neurodegen- reserved erative disorders to systemic amyloidoses. In this review, we identify by CENTRO INVESTIGACIONES BIOLOGICAS on 02/13/07. For personal use only. Annu. Rev. Biochem. 2006.75:333-366. Downloaded from arjournals.annualreviews.org 0066-4154/06/0707- the diseases known to be associated with formation of fibrillar aggre- 0333$20.00 gates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mecha- nisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain inter- actions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior. 333 ANRV277-BI75-14 ARI 8 May 2006 20:57 Contents INTRODUCTION................. 334 Aggregation of Globular Proteins THE ROLE OF AMYLOID-LIKE Can Occur via Partial STRUCTURES IN DISEASE Unfolding..................... 349 AND IN NORMAL BIOLOGY . 335 Aggregation of Globular Proteins Many Human Diseases Are Can Occur via Formation of Associated with Protein Native-Like Oligomers ........ 349 Aggregation ................... 336 A Multitude of Conformational Formation of Amyloid Fibrils Is States Is Accessible to Sometimes Exploited by Living Polypeptide Chains ............ 350 Systems ....................... 339 THE INFLUENCE OF Amyloid Structures Can Serve as SEQUENCE ON AMYLOID Nonchromosomal Genetic FORMATION ................... 352 Elements...................... 339 Hydrophobicity, Charge, and THE STRUCTURES OF Secondary Structure AMYLOID FIBRILS............. 341 Propensities Strongly Influence High-Resolution Structural Studies Amyloid Formation ........... 353 Using Solid-State NMR . .... 341 The Amino Acid Sequence Affects High-Resolution Structural Studies Fibril Structure and Using X-ray Crystallography. 343 Aggregation Rate .............. 353 Other Approaches to Defining the Unfolded Regions Play Critical Structural Properties of Roles in Promoting the Amyloid Fibrils................ 343 Aggregation of Partially Folded Similarities and Differences in States ......................... 355 Fibrillar Structures from Variations in Fibrillar Structure Various Systems ............... 344 Can Be Reconciled by Common The Polymorphism of Amyloid Determinants of the Fibrils ........................ 345 Aggregation Process ........... 356 MECHANISMS OF AMYLOID THE PATHOGENESIS OF FIBRIL FORMATION .......... 346 PROTEIN DEPOSITION Amyloid Formation Occurs via a DISEASES ...................... 357 NucleatedGrowthMechanism. 347 The Search Is on for the Causative Oligomers Preceding Amyloid Agents of Protein Aggregation Fibril Formation: Structured Diseases ...................... 357 by CENTRO INVESTIGACIONES BIOLOGICAS on 02/13/07. For personal use only. Annu. Rev. Biochem. 2006.75:333-366. Downloaded from arjournals.annualreviews.org Protofibrils.................... 347 The Toxicity of Prefibrillar Oligomers Preceding Fibril and Aggregates Results from their Protofibril Formation: Misfolded Nature ............. 358 Unstructured Aggregates ...... 348 PERSPECTIVES ................... 359 INTRODUCTION topic has led to an explosion in the number Writing a review focused on protein misfold- of papers published across a broad spectrum ing and the diseases with which it is related of disciplines, and in part because many of is both an exciting and a challenging activity. the pathological features of the different dis- This is in part because recent interest in this eases, and the characteristics of the proteins 334 Chiti · Dobson ANRV277-BI75-14 ARI 8 May 2006 20:57 with which they are associated, appear at first important ideas that are emerging about the sight to be quite diverse. Despite this diver- pathogenesis of the various protein deposi- sity, it is increasingly evident from the experi- tion diseases and show that, in at least some Protein misfolding: mental data emerging from a wide range of cases, the prefibrillar aggregates, rather than the conversion of a studies that there are some, perhaps many, the mature and stable fibrils into which they protein into a common features in the underlying physico- convert, are the likely origins of pathological structure that differs chemical and biochemical origins of the var- behavior. from its native state ious disorders and, indeed, of the cases in From the evidence that emerges from such Amyloid fibrils: which similar processes contribute positively considerations, we have tried to pull together protein aggregates to biological function. It has been one of our the various threads of this complex subject in having a cross-β structure and other primary objectives during the writing of this an attempt to identify both the common fea- characeristics, e.g., article to explore the extent to which such tures of the various disorders and the differ- specific dye-binding common features can provide the founda- ences that lead to their individual identities. Protein deposition tion on which to develop a deeper under- We also try to show that, in delving into the disease: any standing of the various phenomena associated general phenomenon of protein misfolding, pathological state with protein misfolding and its consequences. considerable light can be shed on the origins associated with the Fortunately, within the past year or two, a of some of the most debilitating and increas- formation of intracellular or variety of excellent reviews and books has ingly common diseases that affect humanity extracellular protein appeared on the more specific features of as well as on the strategies that are likely deposits many aspects of this complex subject, such as to be most effective for their prevention and the two-volume book entitled Protein Misfold- treatment. ing, Aggregation and Conformational Diseases (1). Toprovide a framework on which to build THE ROLE OF AMYLOID-LIKE this article, we first describe the variety of hu- STRUCTURES IN DISEASE AND man diseases that are now thought to arise IN NORMAL BIOLOGY from the misfolding of proteins, particularly A broad range of human diseases arises from those, perhaps the majority, in which mis- the failure of a specific peptide or protein to folding results in the formation of highly or- adopt, or remain in, its native functional con- ganized and generally intractable thread-like formational state. These pathological condi- aggregates termed amyloid fibrils. We point tions are generally referred to as protein mis- out, however, that in addition living organ- folding (or protein conformational ) diseases. They isms can take advantage of the inherent abil- include pathological states in which an im- ity of proteins to form such structures to gen- pairment in the folding efficiency of a given erate novel and diverse biological functions. protein results in a reduction in the quan- Second, we describe the dramatic advances tity of the protein that is available to play by CENTRO INVESTIGACIONES BIOLOGICAS on 02/13/07. For personal use only. Annu. Rev. Biochem. 2006.75:333-366. Downloaded from arjournals.annualreviews.org that have recently been made toward the elu- its normal role. This reduction can arise as cidation of the structures of amyloid fibrils the result of one of several posttranslational at a molecular level and emphasize that our processes, such as an increased probability of knowledge of these structures is no longer degradation via the quality control system of limited to the notion of a fibrillar morphol- the endoplasmic reticulum, as occurs in cys- ogy and an ordered “cross-β” arrangement of tic fibrosis (2), or the improper trafficking of the polypeptide chains of which they are com- a protein, as seen in early-onset emphysema posed. We then describe the progress that is (3). The largest group of misfolding diseases, being made toward understanding the mech- however, is associated with the conversion of anism of aggregation and toward identifying specific peptides or proteins from their soluble the nature of key intermediates in the aggre- functional states ultimately into highly orga- gation process. Finally, we discuss some of the nized fibrillar aggregates. These structures are www.annualreviews.org • Proteins, Amyloid, and Disease 335 ANRV277-BI75-14 ARI 8 May 2006 20:57 generally described as amyloid fibrils or injection or oral administration of preformed plaques when they accumulate extracellu- fibrils from different
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