@misc{10481/55397,
year = {2018},
month = {7},
url = {http://hdl.handle.net/10481/55397},
abstract = {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.},
organization = {This research was funded by Spanish Ministry of Economy and Competitiveness grant number
SAF2015-69796, Junta de Andalucia grant number P11-CTS-07187, the Oxalosis and Hyperoxaluria Foundation
grant number OHF2017, and a fellowship from the Italian Ministery of Instruction University and Research
(RBSI148BK3 to BC).},
publisher = {MDPI},
keywords = {Protein stability},
keywords = {Conformational diseases},
keywords = {Disease-mechanisms},
keywords = {Compensatory mutations},
keywords = {Molecular therapies},
keywords = {Genotype-phenotype correlations},
title = {Evolutionary Divergent Suppressor Mutations in Conformational Diseases},
author = {Mesa Torres, Noel and Betancor-Fernández, Isabel and Oppici, Elisa and Cellini, Barbara and Salido, Eduardo and Pey Rodríguez, Ángel Luis},
}