title: Intrinsic disorder in proteins involved in amyotrophic lateral sclerosis.
abstract: Five structurally and functionally different proteins, an enzyme superoxide dismutase 1 (SOD1), a TAR-DNA binding protein-43 (TDP-43), an RNA-binding protein FUS, a cofilin-binding protein C9orf72, and polypeptides generated as a result of its intronic hexanucleotide expansions, and to lesser degree actin-binding profilin-1 (PFN1), are considered to be the major drivers of amyotrophic lateral sclerosis. One of the features common to these proteins is the presence of significant levels of intrinsic disorder. The goal of this study is to consider these neurodegeneration-related proteins from the intrinsic disorder perspective. To this end, we employed a broad set of computational tools for intrinsic disorder analysis and conducted intensive literature search to gain information on the structural peculiarities of SOD1, TDP-43, FUS, C9orf72, and PFN1 and their intrinsic disorder predispositions, and the roles of intrinsic disorder in their normal and pathological functions.
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Santamaria
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA.
authors.forename: Marwa
authors.initials: M
authors.lastname: Alhothali
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA.
authors.forename: Maria Harreguy
authors.initials: MH
authors.lastname: Alfonso
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA.|USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Breydo
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA. vuversky@health.usf.edu.|USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA. vuversky@health.usf.edu.|Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia. vuversky@health.usf.edu.
authors.forename: Vladimir N
authors.identifier: 0000-0002-4037-5857
authors.initials: VN
authors.lastname: Uversky
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D030562:Databases, Protein; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D051304:Profilins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D064267:Intrinsically Disordered Proteins; C495738:PFN1 protein, human; D051304:Profilins; D011506:Proteins; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Binding-induced folding; FUS; Intrinsically disordered proteins; Neurodegeneration; Polymorphism; Posttranslational modifications; Protein function; Protein structure; Protein–protein interactions; SOD1; TDP-43