SOD1 gene mutations in patients with amyotrophic lateral sclerosis: Potential of method of molecular modeling

Lysogorskaia, E.V.; Rossokhin, A.V.; Abramycheva, N.Y.; Zakharova, M.N.; Illarioshkin, S.N.

Авторы: Lysogorskaia E.V., Rossokhin A.V., Abramycheva N.Yu, Zakharova M.N., Illarioshkin S.N.
Журнал: Molecular Biology
Том: 47
Номер: 5
Год издания: 2013
Издательство: Maik Nauka/Interperiodica Publishing
Местоположение издательства: Russian Federation
Первая страница: 751
Последняя страница: 757
DOI: 10.1134/s0026893313050129
Аннотация: Molecular modeling is a promising method for assessing protein structures that is capable of pre senting an energetically beneficial protein conformation with atomic precision. This method is of great importance for studying molecular interactions and confirming the pathogenic significance of the changes in protein structures caused by particular mutations. In this study, we used molecular modeling to assess muta tions in the SOD1 gene in patients with amyotrophic lateral sclerosis (ALS), a severe neurodegenerative dis order characterized by the loss of spinal and cerebral motor neurons. The product of SOD1 is a cytosolic dimeric enzyme Cu/Zn superoxide dismutase (SOD1) responsible for the detoxification of cellular superox ide radicals. We showed that all eight revealed codingpoint mutations of the gene led to moderate or signif icant changes in SOD1 protein energy. The mutation His49Arg increased protein energy, and the reconstruc tion of the respective model indicated the spatial destabilization of the molecule and abnormal interactions with the metal ion inside the active center. Conversely, the other seven mutations (Gly17Ala, Leu85Val, Asn87Ser, Asp91Ala, Ser106Leu, Glu134Gly, and Leu145Phe) led to a decrease in protein energy and an increase in the spatial stability of SOD 1, which is usually accompanied by an increased tendency for the inert mutant molecule to misfold and demonstrate cellular aggregation. Therefore, the results of the in silico anal ysis of the SOD1 gene mutations confirms that ALS belongs to the class of the socalled conformational dis eases of the central nervous system, a characteristic feature of which is the formation of cytotoxic, insoluble protein inclusions in neurons.
Добавил в систему: Россохин Алексей Владимирович

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SOD1 gene mutations in patients with amyotrophic lateral sclerosis: Potential of method of molecular modelingстатья

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