| Structural highlights
Disease
[SODC_HUMAN] Defects in SOD1 are the cause of amyotrophic lateral sclerosis type 1 (ALS1) [MIM:105400]. ALS1 is a familial form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of cases leading to familial forms.[1] [2] [3] [4] [5] [6] [7] [8] [:][9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
Function
[SODC_HUMAN] Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Publication Abstract from PubMed
ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for approximately 20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease has been difficult, given that more than 140 different SOD1 mutants have been observed in fALS patients. In addition, the molecular origin of sporadic ALS (sALS) is unclear. By dissecting the amino acid sequence of SOD1, we identified four short segments with a high propensity for amyloid fibril formation. We find that fALS mutations in these segments do not reduce their propensity to form fibrils. The atomic structures of two fibril-forming segments from the C terminus, (101)DSVISLS(107) and (147)GVIGIAQ(153), reveal tightly packed beta-sheets with steric zipper interfaces characteristic of the amyloid state. Based on these structures, we conclude that both C-terminal segments are likely to form aggregates if available for interaction. Proline substitutions in (101)DSVISLS(107) and (147)GVIGIAQ(153) impaired nucleation and fibril growth of full-length protein, confirming that these segments participate in aggregate formation. Our hypothesis is that improper protein maturation and incompletely folded states that render these aggregation-prone segments available for interaction offer a common molecular pathway for sALS and fALS.
Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS.,Ivanova MI, Sievers SA, Guenther EL, Johnson LM, Winkler DD, Galaleldeen A, Sawaya MR, Hart PJ, Eisenberg DS Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):197-201. doi:, 10.1073/pnas.1320786110. Epub 2013 Dec 16. PMID:24344300[46]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Orrell RW, Marklund SL, deBelleroche JS. Familial ALS is associated with mutations in all exons of SOD1: a novel mutation in exon 3 (Gly72Ser). J Neurol Sci. 1997 Dec 9;153(1):46-9. PMID:9455977
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- ↑ Ivanova MI, Sievers SA, Guenther EL, Johnson LM, Winkler DD, Galaleldeen A, Sawaya MR, Hart PJ, Eisenberg DS. Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):197-201. doi:, 10.1073/pnas.1320786110. Epub 2013 Dec 16. PMID:24344300 doi:http://dx.doi.org/10.1073/pnas.1320786110
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