Dataset Information

Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degenerative disease in adults and has also been proven to be a type of conformational disease associated with protein misfolding and dysfunction. To date, more than 150 distinct genes have been found to be associated with ALS, among which Superoxide Dismutase 1 (SOD1) is the first and the most extensively studied gene. It has been well-established that SOD1 mutants-mediated toxicity is caused by a gain-of-function rather than the loss of the detoxifying activity of SOD1. Compared with the clear autosomal dominant inheritance of SOD1 mutants in ALS, the potential toxic mechanisms of SOD1 mutants in motor neurons remain incompletely understood. A large body of evidence has shown that SOD1 mutants may adopt a complex profile of conformations and interact with a wide range of client proteins. Here, in this review, we summarize the fundamental conformational properties and the gained interaction partners of the soluble forms of the SOD1 mutants which have been published in the past decades. Our goal is to find clues to the possible internal links between structural and functional anomalies of SOD1 mutants, as well as the relationships between their exposed epitopes and interaction partners, in order to help reveal and determine potential diagnostic and therapeutic targets.

SUBMITTER: Huai J

PROVIDER: S-EPMC6536575 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.

Huai Jisen J Zhang Zhongjian Z

Frontiers in neurology 20190521

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degenerative disease in adults and has also been proven to be a type of conformational disease associated with protein misfolding and dysfunction. To date, more than 150 distinct genes have been found to be associated with ALS, among which Superoxide Dismutase 1 <i>(SOD1)</i> is the first and the most extensively studied gene. It has been well-established that SOD1 mutants-mediated toxicity is caused by a gain-of-function rather ...[more]

PMID: 31164862

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Project description:Cu,Zn superoxide dismutase (SOD1) is a 32 kDa homodimer that converts toxic oxygen radicals in neurons to less harmful species. The dimerization of SOD1 is essential to the stability of the protein. Monomerization increases the likelihood of SOD1 misfolding into conformations associated with aggregation, cellular toxicity, and neuronal death in familial amyotrophic lateral sclerosis (fALS). The ubiquity of disease-associated mutations throughout the primary sequence of SOD1 suggests an important role of physicochemical processes, including monomerization of SOD1, in the pathology of the disease. Herein, we use a first-principles statistical mechanics method to systematically calculate the free energy of dimer binding for SOD1 using molecular dynamics, which involves sequentially computing conformational, orientational, and separation distance contributions to the binding free energy. We consider the effects of two ALS-associated mutations in SOD1 protein on dimer stability, A4V and D101N, as well as the role of metal binding and disulfide bond formation. We find that the penalty for dimer formation arising from the conformational entropy of disordered loops in SOD1 is significantly larger than that for other protein-protein interactions previously considered. In the case of the disulfide-reduced protein, this leads to a bound complex whose formation is energetically disfavored. Somewhat surprisingly, the loop free energy penalty upon dimerization is still significant for the holoprotein, despite the increased structural order induced by the bound metal cations. This resulted in a surprisingly modest increase in dimer binding free energy of only about 1.5 kcal/mol upon metalation of the protein, suggesting that the most significant stabilizing effects of metalation are on folding stability rather than dimer binding stability. The mutant A4V has an unstable dimer due to weakened monomer-monomer interactions, which are manifested in the calculation by a separation free energy surface with a lower barrier. The mutant D101N has a stable dimer partially due to an unusually rigid β-barrel in the free monomer. D101N also exhibits anticooperativity in loop folding upon dimerization. These computational calculations are, to our knowledge, the most quantitatively accurate calculations of dimer binding stability in SOD1 to date.

Dataset Information

Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.

Publications

Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.

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