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Hum Mol Genet. 2017 Sep 15;26(18):3531-3544. doi: 10.1093/hmg/ddx238.

Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution.

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Department of Physical Chemistry, Faculty of Sciences, University of Granada, Granada, Spain.
Institute of General, Inorganic and Theoretical Chemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck, Innsbruck, Austria.
Laboratorio de Estudios Cristalográficos, IACT (CSIC-UGR), Armilla, Granada, Spain.
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avda. del Ferrocarril s/n, 03202 Elche, Alicante, Spain.
Instituto de Biocomputación y Física de los Sistemas Complejos (BIFI), 50009 Zaragoza, Spain.
Centre for Biomedical Research on Rare Diseases (CIBERER), Hospital Universitario de Canarias, Tenerife, Spain.
Department of Biochemistry and Molecular Biology I, Faculty of Sciences and Biomedical Research Center (CIBM), University of Granada, Granada (Spain).
Department of Genetics and Institute of Biotechnology, Faculty of Sciences, and Biomedical Research Center (CIBM), University of Granada, Granada, Spain.
School of Pharmacy and Biomolecular Sciences, The University of Brighton, Brighton, UK.


Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases.

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