Protein Misfolding, Functional Amyloid, and Human Disease Fabrizio Chiti 1 and Christopher M. Dobson 2 1 Dipartimento di Scienze Biochimiche, Universit` a degli Studi di Firenze, I-50134 Firenze, Italy; email: fabrizio.chiti@unifi.it 2 Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom; email: cmd44@cam.ac.uk Annu. Rev. Biochem. 2006. 75:333–66 The Annual Review of Biochemistry is online at biochem.annualreviews.org doi: 10.1146/ annurev.biochem.75.101304.123901 Copyright c  2006 by Annual Reviews. All rights reserved 0066-4154/06/0707- 0333$20.00 Key Words aggregation mechanism, Alzheimer, Parkinson, prion, protein aggregation Abstract Peptides or proteins convert under some conditions from their sol- uble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegen- erative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggre- 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 Annu. Rev. Biochem. 2006.75:333-366. Downloaded from arjournals.annualreviews.org by Universidad Nacional Autonoma de Mexico on 04/15/09. For personal use only.