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

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Abstract

Positive (adaptive) selection has recently been implied in human superoxide dismutase 1 (SOD1), a highly abundant antioxidant protein with energy signaling and antiaging functions, one of very few examples of direct selection on a human protein product (exon); the molecular drivers of this selection are unknown. We mapped 30 extant SOD1 sequences to the recently established mammalian species tree and inferred ancestors, key substitutions, and signatures of selection during the protein’s evolution. We detected elevated substitution rates leading to great apes (Hominidae) at ~1 per 2 million years, significantly higher than in other primates and rodents, although these paradoxically generally evolve much faster. The high evolutionary rate was partly due to relaxation of some selection pressures and partly to distinct positive selection of SOD1 in great apes. We then show that higher stability and net charge and changes at the dimer interface were selectively introduced upon separation from old world monkeys and lesser apes (gibbons). Consequently, human, chimpanzee and gorilla SOD1s have a net charge of −6 at physiological pH, whereas the closely related gibbons and macaques have −3. These features consistently point towards selection against the malicious aggregation effects of elevated SOD1 levels in long-living great apes. The findings mirror the impact of human SOD1 mutations that reduce net charge and/or stability and cause ALS, a motor neuron disease characterized by oxidative stress and SOD1 aggregates and triggered by aging. Our study thus marks an example of direct selection for a particular chemical phenotype (high net charge and stability) in a single human protein with possible implications for the evolution of aging.

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Author notes

  1. Pouria Dasmeh

    Present address: Department of Biochemistry and Cedergren Center for Bioinformatics and Genomics, Faculty of Medicine, University of Montreal, 2900 Edouard-Montpetit, Montreal, QC, H3T 1J4, Canada

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Pouria Dasmeh

  2. Technical University of Denmark, DTU Chemistry, 2800, Kongens Lyngby, Denmark

    Kasper P. Kepp

Authors
  1. Pouria Dasmeh
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  2. Kasper P. Kepp
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Correspondence to Kasper P. Kepp.

Electronic supplementary material

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18_2017_2519_MOESM1_ESM.pdf

Supplementary information: The supporting information file contains the alignment of SOD1 sequences used in this work (Figures S1 and S2); the tree used for rate relaxation analysis as made from DataMonkey (Figure S3); codons detected to be under positive selection using various models (Table S1); branches detected to be under positive selection (Table S2); numerical data from relaxation analysis (Table S3); correlation of benchmarked experimental stability data vs. computed stability changes of SOD1 mutants (Figure S4); numerical data used for this correlation (Table S4); distribution of stability effects for all possible mutations in SOD1 as estimated using Popmusic (Figure S5); all inferred substitutions in the phylogeny from ancestral state reconstruction and computed ∆∆G values and solvent exposure for all sites (Table S5) (PDF 3065 kb)

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Dasmeh, P., Kepp, K.P. Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes. Cell. Mol. Life Sci. 74, 3023–3037 (2017). https://doi.org/10.1007/s00018-017-2519-8

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  • DOI: https://doi.org/10.1007/s00018-017-2519-8

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