title: Uncovering the Binding and Specificity of β-Wrapins for Amyloid-β and α-Synuclein.
abstract: Amyloidogenic proteins amyloid-β peptide (Aβ) and α-synuclein (α-syn) self-assemble into fibrillar amyloid deposits, senile plaques and Lewy bodies, pathological features of Alzheimer's and Parkinson's diseases, respectively. Interestingly, a portion of Alzheimer's disease cases also exhibit aggregation of α-syn into Lewy bodies, and growing evidence also suggests that Aβ and α-syn oligomers are toxic. Therefore, the simultaneous inhibition through sequestration of the two amyloidogenic proteins may constitute a promising therapeutic strategy. Recently discovered β-wrapin proteins pave the way toward this direction as they can inhibit the aggregation and toxicity of both Aβ and α-syn. Here, we used computational methods, primarily molecular dynamics simulations and free energy calculations, to shed light into the key interaction-based commonalities leading to the dual binding properties of β-wrapins for both amyloidogenic proteins, to identify which interactions potentially act as switches diminishing β-wrapins' binding activity for Aβ/α-syn, and to examine the binding properties of the current most potent β-wrapin for Aβ. Our analysis provides insights into the distinct role of the key determinants leading to β-wrapin binding to Aβ and α-syn, and suggests that the Aβ18VFFAED23and α-syn38LYVGSK43are key domains determining the binding specificity of a β-wrapin. Our findings can potentially lead to the discovery of novel therapeutics for Alzheimer's and Parkinson's diseases.
authors.affiliation: Artie McFerrin Department of Chemical Engineering, Texas A&M University , College Station, Texas 77843-3122, United States.
authors.forename: Asuka A
authors.initials: AA
authors.lastname: Orr
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40204 Düsseldorf, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Wördehoff
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40204 Düsseldorf, Germany.|Institute of Structural Biochemistry (ICS-6), Research Centre Jülich , 52425 Jülich, Germany.
authors.forename: Wolfgang
authors.identifier: 0000-0003-4301-5416
authors.initials: W
authors.lastname: Hoyer
authors.affiliation: Artie McFerrin Department of Chemical Engineering, Texas A&M University , College Station, Texas 77843-3122, United States.
authors.forename: Phanourios
authors.identifier: 0000-0002-3342-2651
authors.initials: P
authors.lastname: Tamamis
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000906:Antibodies / Q000737:chemistry*; D000918:Antibody Specificity; D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D015202:Protein Engineering; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012996:Solutions; D013816:Thermodynamics; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000906:Antibodies; D012996:Solutions; D051844:alpha-Synuclein