Fibrillogenesis of Huntingtin and Other Glutamine Containing Proteins
This chapter focuses on the aggregation of glutamine containing peptides and proteins with an emphasis on huntingtin protein, whose aggregation leads to the development of Huntington’s disease. The kinetics that leads to the formation of amyloids, the str
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Fibrillogenesis of Huntingtin and Other Glutamine Containing Proteins Yuri L. Lyubchenko, Alexey V. Krasnoslobodtsev and Sorin Luca
Abstract This chapter focuses on the aggregation of glutamine containing peptides and proteins with an emphasis on huntingtin protein, whose aggregation leads to the development of Huntington’s disease. The kinetics that leads to the formation of amyloids, the structure of aggregates of various types and the morphological mechanical properties of amyloid fibrils are described. The kinetics of amyloid fibril formation has been proposed to follow a nucleation dependent polymerization model, dependent upon the size of the nucleus. This model and the effect of the polyglutamine length on the nucleus size are reviewed. Aggregate structure is characterized at two different levels. The atomic-scale resolution structure of fibrillar and crystalline aggregates of polyglutamine containing proteins and peptides was determined by X-ray crystallography and solid-state nuclear magnetic resonance (NMR). The chapter outlines the results obtained by both these techniques. Atomic force microscopy (AFM) was instrumental in elucidating the morphology of fibrils, their organization and assembly. The chapter also discusses the high stability of amyloid fibrils, including their mechanical properties as revealed by AFM. Keywords Huntington’s disease · Amyloids · Self-assembly · Fibrillogenesis · Atomic Force Microscopy · AFM · Solid-state NMR Abbreviations Htt Aβ AFM NMR EPR
Huntingtin protein Amyloid-beta Atomic Force Microscopy Nuclear magnetic resonance Electron paramagnetic resonance
Y. L. Lyubchenko () · A. V. Krasnoslobodtsev · S. Luca Department of Pharmaceutical Sciences, Nanoimaging Core Facility College of Pharmacy, University of Nebraska Medical Center, COP 1012, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA e-mail: [email protected] A. V. Krasnoslobodtsev e-mail: [email protected] S. Luca e-mail: [email protected] J. R. Harris (ed.), Protein Aggregation and Fibrillogenesis in Cerebral 225 and Systemic Amyloid Disease, Subcellular Biochemistry 65, DOI 10.1007/978-94-007-5416-4_10, © Springer Science+Business Media Dordrecht 2012
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Introduction
Misfolding and aggregation of proteins is a common thread linking a number of important human health problems associated with protein deposition diseases, including neurodegenerative disorders such as Parkinson’s disease, Down’s syndrome, Alzheimer’s and Huntington’s diseases, systemic and localized amyloidoses and transmissible encephalopathies (Dobson 2004b). Each of these diseases is associated with misfolding and aggregation of one or two specific proteins. Altogether, the accumulation of abnormal protein aggregates exerts toxicity by disrupting intracellular transport, overwhelming protein degradation pathways, and/or disturbing vital cellular functions. Since protein refolding is frequently accompanied by transient association of partially folded intermediates, the propensity to aggregate is considere
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