TY - JOUR
T1 - Insight into the Autosomal-Dominant Inheritance Pattern of SOD1-Associated ALS from Native Mass Spectrometry
AU - Cveticanin, Jelena
AU - Mondal, Tridib
AU - Meiering, Elizabeth M.
AU - Sharon, Michal
AU - Horovitz, Amnon
N1 - Part of this work was carried out while E.M.M. was an Erna and Jakob Michael Visiting Professor at the Weizmann Institute. E.M.M. is grateful for support from the Natural Sciences and Engineering Research Council of Canada. A.H. is grateful for support from the Helen & Milton A. Kimmelman Center for Biomolecular Structure and Assembly and the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research. A.H. is an incumbent of the Carl and Dorothy Bennett Professorial Chair in Biochemistry. M.S. is grateful for the financial support of a starting grant from the European Research Council (Horizon 2020) no. 636752 and an Israel Science Foundation grant no. 300/17. M.S. is the incumbent of the Aharon and Ephraim Katzir Memorial Professorial Chair.
PY - 2020/11/20
Y1 - 2020/11/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85096005324&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2020.09.025
DO - 10.1016/j.jmb.2020.09.025
M3 - مقالة
C2 - 33058881
SN - 0022-2836
VL - 432
SP - 5995
EP - 6002
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 23
ER -