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Genes 2018, 9(7), 352;

Evolutionary Divergent Suppressor Mutations in Conformational Diseases

Department of Physical Chemistry, University of Granada, 18010 Granada, Spain
Hospital Universitario de Canarias, Center for Rare Diseases (CIBERER), University of La Laguna, 38320 Tenerife, Spain
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, 37134 Verona, Italy
Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
Author to whom correspondence should be addressed.
Received: 12 June 2018 / Revised: 9 July 2018 / Accepted: 11 July 2018 / Published: 13 July 2018
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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Neutral and adaptive mutations are key players in the evolutionary dynamics of proteins at molecular, cellular and organismal levels. Conversely, largely destabilizing mutations are rarely tolerated by evolution, although their occurrence in diverse human populations has important roles in the pathogenesis of conformational diseases. We have recently proposed that divergence at certain sites from the consensus (amino acid) state during mammalian evolution may have rendered some human proteins more vulnerable towards disease-associated mutations, primarily by decreasing their conformational stability. We herein extend and refine this hypothesis discussing results from phylogenetic and structural analyses, structure-based energy calculations and structure-function studies at molecular and cellular levels. As proof-of-principle, we focus on different mammalian orthologues of the NQO1 (NAD(P)H:quinone oxidoreductase 1) and AGT (alanine:glyoxylate aminotransferase) proteins. We discuss the different loss-of-function pathogenic mechanisms associated with diseases involving the two enzymes, including enzyme inactivation, accelerated degradation, intracellular mistargeting, and aggregation. Last, we take into account the potentially higher robustness of mammalian orthologues containing certain consensus amino acids as suppressors of human disease, and their relation with different intracellular post-translational modifications and protein quality control capacities, to be discussed as sources of phenotypic variability between human and mammalian models of disease and as tools for improving current therapeutic approaches. View Full-Text
Keywords: protein stability; conformational diseases; disease-mechanisms; compensatory mutations; molecular therapies; genotype-phenotype correlations protein stability; conformational diseases; disease-mechanisms; compensatory mutations; molecular therapies; genotype-phenotype correlations

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Mesa-Torres, N.; Betancor-Fernández, I.; Oppici, E.; Cellini, B.; Salido, E.; Pey, A.L. Evolutionary Divergent Suppressor Mutations in Conformational Diseases. Genes 2018, 9, 352.

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