Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

Dasmeh, Pouria; Kepp, Kasper Planeta

doi:10.1007/s00018-017-2519-8

Cited by 18 publications

(22 citation statements)

References 117 publications

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“…Evolution appears to have very quickly traded CCS stability for SOD1 stability. In great apes, including humans, this effect is particularly pronounced, with SOD1 having undergone strong positive selection to limit instability and thereby extend life span [39]. In contrast, a weakened CCS dimer interface does not appear to swamp cellular proteostasis machinery in the same way that SOD1 dimer interface destabilising mutations do [20,40], possibly due to reduced relative expression [41] or more efficient degradation.…”

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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“…SOD1 aggregates in sporadic ALS, and mutations cause severe early-onset familial ALS (FALS) (Dasmeh and Kepp, 2017;Kepp, 2015Kepp, , 2014. ALS patients experience increased resting energy expenditure that has not been rationalized (Bouteloup et al, 2009) , (Genton et al, 2011), but fits Equation (15) since SOD1 mutants almost invariably decrease stability and thus increase the pool of misfolding proteins requiring turnover.…”

Section: Support For the Model: Energy In The Healthy Brain And In DImentioning

confidence: 99%

A quantitative model of human neurodegenerative diseases involving protein aggregation

Kepp

2019

Neurobiology of Aging

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“…The mechanistic basis for the theory is that (i) protein degradation increases many-fold with the lack of structure and partial unfolding in protein copies (Gsponer et al ., 2008) and (ii) the cost of protein turnover is more than half of total metabolic costs in growing microorganisms (Harold, 1987), and at least 20% in humans (Waterlow, 1995). Accordingly, any increase in these costs reduces the energy available for other energy-demanding processes, notably reproduction (fitness) of microorganisms (Dasmeh and Kepp, 2017) and cell signaling (cognition) in higher organisms (Kepp, 2019). One of many implications of the theory is that selection against misfolded proteins and toxicity of misfolding proteins measured in cell viability assays is not due to a specific toxic molecular mode of action as widely assumed, but to the generic adenosine triphosphate (ATP) burden of turning over the misfolded proteins within the cell .…”

Section: The Theory Of Proteome Cost Minimizationmentioning

confidence: 99%

Survival of the cheapest: how proteome cost minimization drives evolution

Kepp

2020

Quart. Rev. Biophys.

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Darwin's theory of evolution emphasized that positive selection of functional proficiency provides the fitness that ultimately determines the structure of life, a view that has dominated biochemical thinking of enzymes as perfectly optimized for their specific functions. The 20th-century modern synthesis, structural biology, and the central dogma explained the machinery of evolution, and nearly neutral theory explained how selection competes with random fixation dynamics that produce molecular clocks essential e.g. for dating evolutionary histories. However, quantitative proteomics revealed that selection pressures not relating to optimal function play much larger roles than previously thought, acting perhaps most importantly via protein expression levels. This paper first summarizes recent progress in the 21st century toward recovering this universal selection pressure. Then, the paper argues that proteome cost minimization is the dominant, underlying ‘non-function’ selection pressure controlling most of the evolution of already functionally adapted living systems. A theory of proteome cost minimization is described and argued to have consequences for understanding evolutionary trade-offs, aging, cancer, and neurodegenerative protein-misfolding diseases.

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Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

Cited by 18 publications

References 117 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

A quantitative model of human neurodegenerative diseases involving protein aggregation

Survival of the cheapest: how proteome cost minimization drives evolution

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