Lipid-associated aggregate formation of superoxide dismutase-1 is initiated by membrane-targeting loops

Chng, Choon-Peng; Strange, R.W.

doi:10.1002/prot.24688

Cited by 10 publications

(8 citation statements)

References 68 publications

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“…Thus, hCCS membrane association is mediated by the combination of globular domains I and II together with the increased interaction surface area provided by domain III–mediated dimerisation. While metal-free, disulphide-reduced wild-type hSOD1 associates with and even penetrates lipid membrane [37,38], on zinc binding, this association is greatly reduced (Fig 5C). Thus, the substrate for hCCS provides little additional membrane attraction, and half of the interfacial interacting surface provided by hCCS homodimerisation is lost on heterodimerisation.…”

Section: Resultsmentioning

confidence: 99%

Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS

et al. 2019

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Superoxide dismutase-1 (SOD1) maturation comprises a string of posttranslational modifications which transform the nascent peptide into a stable and active enzyme. The successive folding, metal ion binding, and disulphide acquisition steps in this pathway can be catalysed through a direct interaction with the copper chaperone for SOD1 (CCS). This process confers enzymatic activity and reduces access to noncanonical, aggregation-prone states. Here, we present the functional mechanisms of human copper chaperone for SOD1 (hCCS)–catalysed SOD1 activation based on crystal structures of reaction precursors, intermediates, and products. Molecular recognition of immature SOD1 by hCCS is driven by several interface interactions, which provide an extended surface upon which SOD1 folds. Induced-fit complexation is reliant on the structural plasticity of the immature SOD1 disulphide sub-loop, a characteristic which contributes to misfolding and aggregation in neurodegenerative disease. Complexation specifically stabilises the SOD1 disulphide sub-loop, priming it and the active site for copper transfer, while delaying disulphide formation and complex dissociation. Critically, a single destabilising amino acid substitution within the hCCS interface reduces hCCS homodimer affinity, creating a pool of hCCS available to interact with immature SOD1. hCCS substrate specificity, segregation between solvent and biological membranes, and interaction transience are direct results of this substitution. In this way, hCCS-catalysed SOD1 maturation is finessed to minimise copper wastage and reduce production of potentially toxic SOD1 species.

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Section: Resultsmentioning

confidence: 99%

Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS

et al. 2019

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“…501 AA simulations of cytotoxic demetallated copper-zinc superoxide dismutase 1 found that the protein was both able to adsorb onto PC bilayers, using its metal binding loops, and to complex with clumps of octanol in solution. 502 Another example is PTEN, which hydrolyzes PIP 3 to PIP 2 and contains both a tyrosine phosphatase domain and a membrane binding C2 domain. PTEN interaction with the membrane has been studied using both CG and AA simulations.…”

Section: Membrane-bound Enzymesmentioning

confidence: 99%

Characterization of Lipid–Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation

et al. 2019

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The cellular membrane constitutes one of the most fundamental compartments of a living cell, where key processes such as selective transport of material and exchange of information between the cell and its environment are mediated by proteins that are closely associated with the membrane. The heterogeneity of lipid composition of biological membranes and the effect of lipid molecules on the structure, dynamics, and function of membrane proteins are now widely recognized. Characterization of these functionally important lipid-protein interactions with experimental techniques is however still prohibitively challenging. Molecular dynamics (MD) simulations offer a powerful complementary approach with sufficient temporal and spatial resolutions to gain atomic-level structural information and energetics on lipid-protein interactions. In this review, we aim to provide a broad survey of MD simulations focusing on exploring lipidprotein interactions and characterizing lipid-modulated protein structure and dynamics that have been successful in providing novel insight into the mechanism of membrane protein function.

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“…SOD1, particularly the metal-free state, incorporates within biological membranes and disorders lipid packing (Petkau and Chelack, 1976; Petkau and Copps, 1979; Lepock et al ., 1981). Chng and Strange (2014) used molecular dynamics simulations to show how residues in the conformationally dynamic electrostatic and zinc-binding loops bind octanol and mediate interactions with bilayer surfaces. A C-terminal SOD1 truncation at Leu126 facilitates the adoption of a membrane-penetrant helical structure with several transmembrane helices (Lim et al ., 2015), and similarly, Ala4Val SOD1 self-association created a tetramer capable of functioning as an integral membrane ion channel (Allen et al ., 2012 a ).…”

Section: Sod1 Aggregation In Alsmentioning

confidence: 99%

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

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Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

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Lipid-associated aggregate formation of superoxide dismutase-1 is initiated by membrane-targeting loops

Cited by 10 publications

References 68 publications

Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS

Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS

Characterization of Lipid–Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

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