title: Computational methods for identifying a layered allosteric regulatory mechanism for ALS-causing mutations of Cu-Zn superoxide dismutase 1.
abstract: The most prominent form of familial amyotrophic lateral sclerosis (fALS, Lou Gehrig's Disease) is caused by mutations of Cu-Zn superoxide dismutase 1 (SOD1). SOD1 maintains antioxidant activity under fALS causing mutations, suggesting that the mutations introduce a new, toxic, function. There are 100+ such known mutations that are chemically diverse and spatially distributed across the structure. The common phenotype leads us to propose an allosteric regulatory mechanism hypothesis: SOD1 mutants alter the correlated dynamics of the structure and differentially signal across an inherent allosteric network, thereby driving the disease mechanism at varying rates of efficiency. Two recently developed computational methods for identifying allosteric control sites are applied to the wild type crystal structure, 4 fALS mutant crystal structures, 20 computationally generated fALS mutants and 1 computationally generated non-fALS mutant. The ensemble of mutant structures is used to generate an ensemble of dynamics, from which two allosteric control networks are identified. One network is connected to the catalytic site and thus may be involved in the natural antioxidant function. The second allosteric control network has a locus bordering the dimer interface and thus may serve as a mechanism to modulate dimer stability. Though the toxic function of mutated SOD1 is unknown and likely due to several contributing factors, this study explains how diverse mutations give rise to a common function. This new paradigm for allostery controlled function has broad implications across allosteric systems and may lead to the identification of the key chemical activity of SOD1-linked ALS.
authors.affiliation: Department of Molecular, Microbial and Structural Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. schuyler@uchc.edu
authors.forename: Adam D
authors.initials: AD
authors.lastname: Schuyler
authors.forename: Heather A
authors.initials: HA
authors.lastname: Carlson
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000494:Allosteric Regulation; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology*; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1