title: Superoxide Dismutase 1 (SOD1)-Derived Peptide Inhibits Amyloid Aggregation of Familial Amyotrophic Lateral Sclerosis SOD1 Mutants.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the death of the upper and lower motor neurons. Superoxide dismutase 1 (SOD1) is an ALS pathogenic protein, whose misfolding results in the formation of amyloid aggregates. The mechanism underlying SOD1 pathogenesis in ALS remains obscure, but one possible mechanism involves gain-of-interaction, in which the misfolded soluble SOD1 forms abnormal protein-protein interactions (PPIs) with various cellular proteins, including with other SOD1 molecules, thereby interfering with their function. The structural basis of this gain-of-interaction mechanism is unknown. Here, we characterized the backbone dynamics landscape of misfolded SOD1 to pinpoint surface areas predisposed to aberrant PPIs. This analysis enabled us to formulate a working hypothesis for the mechanism of the gain-of-function of misfolded SOD1, according to which an abnormal PPI potential results from the increased mobility of the SOD1 surface backbone. Guided by the backbone dynamics landscape, we have identified a SOD1-derived peptide that can bind SOD1 proteins and divert the typical amyloid aggregation of ALS-related SOD1 mutants toward a potentially less toxic amorphous aggregation pathway.
authors.affiliation: Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.|National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Victor
authors.initials: V
authors.lastname: Banerjee
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Tom
authors.initials: T
authors.lastname: Shani
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Katzman
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.|National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Vyazmensky
authors.affiliation: Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.|National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Niv
authors.initials: N
authors.lastname: Papo
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Adrian
authors.initials: A
authors.lastname: Israelson
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.|National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer-Sheva 8410501, Israel.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Engel
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis (ALS); amyloid aggregation; gain-of-function; stability patches; steered molecular dynamics (SMD); superoxide dismutase 1 (SOD1)