Abstract
Intrinsically disordered proteins or regions of proteins lack a well-defined structure, yet they carry out important functions often associated with the regulation of cell cycle and transcription. Due to these central roles in key cellular processes, their mutations are frequently involved in neurodegenerative diseases. These diseases are usually caused by the structural transition of disordered proteins to insoluble, highly ordered deposits termed amyloids, such a fate has been described in the case of Aβ peptide and tau protein in Alzheimer’s disease, α-synuclein in Parkinson’s disease or the polyglutamin stretch of huntingtin in Huntington’s disease and the prion protein in prion diseases. Due to the involvement of critical conformational change, these diseases are often denoted as “protein misfolding” diseases. Here we provide a brief overview of the rapidly expanding field of protein disorder to provide a conceptual background for the discussion of the essence of molecular mechanisms of these diseases. We will provide a brief overview of the field in general, directing focus on the tendency of disordered proteins for aggregation in vitro and also in vivo. We will provide some details on neurodegenerative diseases and the proteins involved. It will be shown that the underlying phenomenon of “misfolding” may also result in altering the normal function of proteins (physiological prions). We will wrap up the story by showing that the conformational transition occurs via partially ordered intermediates, which lead to a highly structured cross-β state in amyloids.
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Csizmók, V., Tompa, P. (2009). Structural Disorder and Its Connection with Misfolding Diseases. In: Ovádi, J., Orosz, F. (eds) Protein Folding and Misfolding: Neurodegenerative Diseases. Focus on Structural Biology, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9434-7_1
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