6flh | pdb_00006flh

Monomeric Human Cu,Zn Superoxide dismutase, SOD1 7+7, apo form

spinqualitylabelsall models 6flh, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6flh is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, SO4 Activity: Superoxide dismutase, with EC number 1.15.1.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. [:] Function [SODC_HUMAN] Destroys radicals which are normally produced within the cells and which are toxic to biological systems. Publication Abstract from PubMed A conspicuous feature of the ALS-associated protein SOD1 is that its maturation into a functional enzyme relies on local folding of two disordered loops into a catalytic subdomain. To drive the disorder-to-order transition, the protein employs a single Zn2+ ion. The question is then if the entropic penalty of maintaining such disordered loops in the immatureapoSOD1 monomer is large enough to explain its unusually low stability, slow folding and pathological aggregation in ALS. To find out, we determined the effects of systematically altering the SOD1-loop lengths by protein re-design. The results show that the loops destabilise the apoSOD1 monomer by approximately 3 kcal/mol, rendering the protein marginally stable and accounting for its aggregation behaviour. Yet the effect on the global folding kinetics remains much smaller with a transition-state destabilisation of < 1 kcal/mol. Notably, this 1/3 transition-state to folded-state stability ratio provides a clear-cut example of the enigmatic disagreement between the Leffler alpha value from loop-length alterations (typically 1/3) and the 'standard' reaction coordinates based on solvent perturbations (typically > 2/3). Reconciling the issue, we demonstrate that the disagreement disappears when accounting for the progressive loop shortening that occurs along the folding pathway. The approach assumes a consistent Flory loop entropy scaling factor of c = 1.48 for both equilibrium and kinetic data, and has the added benefit of verifying the tertiary interactions of the folding nucleus as determined by phi-value analysis. Thus, SOD1 represents not only a case where evolution of key catalytic function has come with the drawback of a destabilised apo state, but also stands out as a well-suited model system for exploring the physicochemical details of protein self organisation. The cost of long catalytic loops in folding and stability of the ALS-associated protein SOD1.,Yang F, Wang H, Logan DT, Mu X, Danielsson J, Oliveberg M J Am Chem Soc. 2018 Oct 25. doi: 10.1021/jacs.8b08141. PMID:30359015 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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