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      Discovering Putative Prion-Like Proteins in Plasmodium falciparum: A Computational and Experimental Analysis

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          Abstract

          Prions are a singular subset of proteins able to switch between a soluble conformation and a self-perpetuating amyloid state. Traditionally associated with neurodegenerative diseases, increasing evidence indicates that organisms exploit prion-like mechanisms for beneficial purposes. The ability to transit between conformations is encoded in the so-called prion domains, long disordered regions usually enriched in glutamine/asparagine residues. Interestingly, Plasmodium falciparum, the parasite that causes the most virulent form of malaria, is exceptionally rich in proteins bearing long Q/N-rich sequence stretches, accounting for roughly 30% of the proteome. This biased composition suggests that these protein regions might correspond to prion-like domains (PrLDs) and potentially form amyloid assemblies. To investigate this possibility, we performed a stringent computational survey for Q/N-rich PrLDs on P. falciparum. Our data indicate that ∼10% of P. falciparum protein sequences have prionic signatures, and that this subproteome is enriched in regulatory proteins, such as transcription factors and RNA-binding proteins. Furthermore, we experimentally demonstrate for several of the identified PrLDs that, despite their disordered nature, they contain inner short sequences able to spontaneously self-assemble into amyloid-like structures. Although the ability of these sequences to nucleate the conformational conversion of the respective full-length proteins should still be demonstrated, our analysis suggests that, as previously described for other organisms, prion-like proteins might also play a functional role in P. falciparum.

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          Most cited references 55

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          Discovery of gene function by expression profiling of the malaria parasite life cycle.

          The completion of the genome sequence for Plasmodium falciparum, the species responsible for most malaria human deaths, has the potential to reveal hundreds of new drug targets and proteins involved in pathogenesis. However, only approximately 35% of the genes code for proteins with an identifiable function. The absence of routine genetic tools for studying Plasmodium parasites suggests that this number is unlikely to change quickly if conventional serial methods are used to characterize encoded proteins. Here, we use a high-density oligonucleotide array to generate expression profiles of human and mosquito stages of the malaria parasite's life cycle. Genes with highly correlated levels and temporal patterns of expression were often involved in similar functions or cellular processes.
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            The genome of the social amoeba Dictyostelium discoideum.

            The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.
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              FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded.

              An easy-to-use, versatile and freely available graphic web server, FoldIndex is described: it predicts if a given protein sequence is intrinsically unfolded implementing the algorithm of Uversky and co-workers, which is based on the average residue hydrophobicity and net charge of the sequence. FoldIndex has an error rate comparable to that of more sophisticated fold prediction methods. Sliding windows permit identification of large regions within a protein that possess folding propensities different from those of the whole protein.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                07 August 2018
                2018
                : 9
                Affiliations
                1Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona , Barcelona, Spain
                2Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona , Barcelona, Spain
                3Centre for Genomic Regulation, The Barcelona Institute of Science and Technology , Barcelona, Spain
                4Universitat Pompeu Fabra , Barcelona, Spain
                5Nanomalaria Group, Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology , Barcelona, Spain
                6Barcelona Institute for Global Health, Barcelona Centre for International Health Research (Hospital Clínic – Universitat de Barcelona) , Barcelona, Spain
                7Institute of Nanoscience and Nanotechnology, University of Barcelona , Barcelona, Spain
                Author notes

                Edited by: Rustam Aminov, University of Aberdeen, United Kingdom

                Reviewed by: Nyssa Drinkwater, Monash University, Australia; Thomas Dandekar, Universität Würzburg, Germany

                *Correspondence: Salvador Ventura, salvador.ventura@ 123456uab.es

                These authors have contributed equally to this work.

                This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2018.01737
                6090025
                Copyright © 2018 Pallarès, de Groot, Iglesias, Sant’Anna, Biosca, Fernàndez-Busquets and Ventura.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 90, Pages: 13, Words: 0
                Funding
                Funded by: Ministerio de Economía y Competitividad 10.13039/501100003329
                Award ID: BIO2016-783-78310-R
                Funded by: Institució Catalana de Recerca i Estudis Avançats 10.13039/501100003741
                Award ID: ICREA ACADEMIA 2015
                Categories
                Microbiology
                Original Research

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