| 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
The origin and biological role of dynamic motions of folded enzymes is not yet fully understood. In this study, we examine the molecular determinants for the dynamic motions within the beta-barrel of superoxide dismutase 1 (SOD1), which previously were implicated in allosteric regulation of protein maturation and also pathological misfolding in the neurodegenerative disease amyotrophic lateral sclerosis. Relaxation-dispersion NMR, hydrogen/deuterium exchange, and crystallographic data show that the dynamic motions are induced by the buried H43 side chain, which connects the backbones of the Cu ligand H120 and T39 by a hydrogen-bond linkage through the hydrophobic core. The functional role of this highly conserved H120-H43-T39 linkage is to strain H120 into the correct geometry for Cu binding. Upon elimination of the strain by mutation H43F, the apo protein relaxes through hydrogen-bond swapping into a more stable structure and the dynamic motions freeze out completely. At the same time, the holo protein becomes energetically penalized because the twisting back of H120 into Cu-bound geometry leads to burial of an unmatched backbone carbonyl group. The question then is whether this coupling between metal binding and global structural motions in the SOD1 molecule is an adverse side effect of evolving viable Cu coordination or plays a key role in allosteric regulation of biological function, or both?
Global structural motions from the strain of a single hydrogen bond.,Danielsson J, Awad W, Saraboji K, Kurnik M, Lang L, Leinartaite L, Marklund SL, Logan DT, Oliveberg M Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3829-34. doi:, 10.1073/pnas.1217306110. Epub 2013 Feb 19. PMID:23431167[46]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Danielsson J, Awad W, Saraboji K, Kurnik M, Lang L, Leinartaite L, Marklund SL, Logan DT, Oliveberg M. Global structural motions from the strain of a single hydrogen bond. Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3829-34. doi:, 10.1073/pnas.1217306110. Epub 2013 Feb 19. PMID:23431167 doi:http://dx.doi.org/10.1073/pnas.1217306110
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