Insight into the Autosomal-Dominant Inheritance Pattern of SOD1-Associated ALS from Native Mass Spectrometry. Issue 23 (20th November 2020)

• Record Type: Journal Article
• Authors: Cveticanin, Jelena; Mondal, Tridib; Meiering, Elizabeth M.; Sharon, Michal; Horovitz, Amnon
• Is Part Of: Journal of molecular biology. Volume 432:Issue 23(2020)
• Page Start: 5995
• Page End: 6002
• Publication Date: 2020-11-20
• Subjects: native mass spectrometry -- superoxide dismutase -- amyotrophic lateral sclerosis -- double-mutant cycles -- protein interactions; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.09.025
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Co-expressed wild-type and mutant SOD1 subunits form homo- and heterodimers. Native mass spectrometry can be used to determine a bias in subunit association. Coupling constants provide a measure of the bias in subunit association. Coupling constants for ALS-causing mutants correlate positively with disease duration. SOD1 heterodimerization greatly increases ALS disease severity. Abstract: About 20% of all familial amyotrophic lateral sclerosis (ALS) cases are associated with mutations in superoxide dismutase (SOD1), a homodimeric protein. The disease has an autosomal-dominant inheritance pattern. It is, therefore, important to determine whether wild-type and mutant SOD1 subunits self-associate randomly or preferentially. A measure for the extent of bias in subunit association is the coupling constant determined in a double-mutant cycle type analysis. Here, cell lysates containing co-expressed wild-type and mutant SOD1 subunits were analyzed by native mass spectrometry to determine these coupling constants. Strikingly, we find a linear positive correlation between the coupling constant and the reported average duration of the disease. Our results indicate that inter-subunit communication and a preference for heterodimerization greatly increase the disease severity.