Prion Amyloids Or Prions?

View metadata, citation and similar papers at core.ac.uk brought to you by CORE This article was downloaded by: [KU Leuven University Library] provided by Lirias On: 04 June 2015, At: 04:08 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Prion Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kprn20 Amyloids or Prions? That is the Question Raimon Sabatea, Frederic Rousseaubc, Joost Schymkowitzbc, Cristina Batlled & Salvador Venturad a Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Avda. Joan XXIII s/n, E- 08028-Barcelona, Spain b VIB Switch Laboratory, VIB, Leuven, Belgium c Department for Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium d Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular. Universitat Aut∫noma de Barcelona, 08193 Bellaterra, Barcelona, Spain Accepted author version posted online: 03 Jun 2015. Click for updates To cite this article: Raimon Sabate, Frederic Rousseau, Joost Schymkowitz, Cristina Batlle & Salvador Ventura (2015): Amyloids or Prions? That is the Question, Prion, DOI: 10.1080/19336896.2015.1053685 To link to this article: http://dx.doi.org/10.1080/19336896.2015.1053685 Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also. PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions Amyloids or Prions? That is the Question. Raimon Sabate1,#, Frederic Rousseau2,3,#, Joost Schymkowitz2,3,# Cristina Batlle4 and Salvador Ventura4,* 1Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Avda. Joan XXIII s/n, E- 08028-Barcelona, Spain 2VIB Switch Laboratory, VIB, Leuven, Belgium 3Department for Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium 4Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular. Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain Running tittle: Determinants of Prion Formation #Equal contribution *Correspondence: Salvador Ventura, Institut de Biotecnologia i de Biomedicina, Parc de Recerca UAB, Mòdul B, Universitat Autònoma de Barcelona, E-08193 Bellaterra (Barcelona), [email protected] ABSTRACT Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allows to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation. Downloaded by [KU Leuven University Library] at 04:08 04 June 2015 Keywords prions, amyloids, protein intrinsic disorder, Q/N-rich domains, yeast, neurodegenerative diseases. Abbreviations Alzheimer’s disease, AD; transmissible spongiform encephalopathy, TSE; Parkinson’s disease, PD; Creutzfeldt-Jakob disease, CJD; familial amyotrophic lateral sclerosis, fALS; prion forming domain, PFD; 1 In the cell, proteins attain the native structure through a delicate and balanced network of interactions, where protein folding and aggregation exert as competing pathways1, 2. In a protein energy landscape, amyloid-like aggregates represent an energy minimum, being usually thermodynamically more stable than the native conformation. This has lead to the hypothesis that the amyloid conformation reflects a universal mode of assembly of polypeptide chains and that native protein conformations are evolutionary selected metastable states2. Amyloids are aggregates displaying fibrillar structure, which is constituted by repetitions of a specific protein in a regular β-sheet conformation that runs perpendicular to the fibril axis3. In humans, amyloids are linked to diseases ranging from neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Creutzfeldt-Jakob disease (CJD), to non-neuronal systemic and localized disorders3. On the other hand functional amyloids, i.e. proteins that exploit the amyloid fold for evolutionary selected biological functions, have been discovered in diverse species, including human4. The roles fulfilled by these functional amyloids range from obligate amyloid structures required for scaffolding and/or movement to conditional amyloids such as the yeast prions that can be triggered by environmental factors5. Whether obligate or conditional, the natural selection of amyloid structure as a functional motif indicates that these properties are likely sequence specific. Whereas the attainment and sustainment of the native structure relies on cooperative interactions involving most, if not all, of the sequence of a protein domain6, 7, the now widely accepted ‘short stretch hypothesis’ states that amyloid formation in contrast is nucleated by short regions of the amino acid sequence named aggregation hot-spots (HS), Aggregation Prone Regions (APR) or Aggregation Prone Sequences (APS)8, 9. The short stretch Downloaded by [KU Leuven University Library] at 04:08 04 June 2015 model led to the development of over twenty algorithms that more or less successfully predict protein aggregation and amyloid formation based on the identification of specific b-aggregation and amyloid-prone regions in the polypeptide sequences 10-12. In disease-associated amyloids these regions are generally between 5 and 10 residues in length 13 . Prions are considered a subclass of amyloids in which protein aggregation becomes self- perpetuating and infectious. The phenomenon is known mostly as a neuronal pathology in mammals but in fungi prions play a crucial role in epigenetic inheritance 14-16. Importantly, despite the overlapping conformational properties of amyloids and prions, only a handful of 2 amyloids are currently considered to display at least partial prion capacity under natural conditions 16. As a result, b-aggregation and amyloid predictors are still a long way from correctly detecting prion sequences in proteomes 17. In fact, the sequence characteristics that make a protein sequence a prion have been elusive for years. Moreover, at first glance, the sequence features conferring prion capacity to prion protein in mammals (PrP) appear to differ remarkably from those determining prion behaviour in fungi. Yeast prions are the best characterized transmissible amyloids, thus being excellent model systems to address the determinants of concomitant amyloid formation and propagation 18. In these proteins, prion formation from an initially soluble state involves a structural amyloid conversion driven by specific, relatively large, unstructured domains enriched in glutamine/asparagine (Q/N) residues 18. Interestingly, protein domains displaying this sequence signature are over-represented in eukaryotic proteomes relative to prokaryotes, suggesting that prion-like conformational transition might have evolved as a mechanism for regulating gene function at the protein level in eukaryotes19. It should be mentioned, however, that PrP, the archetypical mammalian prion, lacks these sequential features. In order to explore the repertoire of prion proteins in Saccharomyces cerevisiae the Lindquist group conducted a genome-wide bioinformatics survey using a hidden Markov

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