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

Encarnación Medina-Carmona, Julian E. Fuchs, Jose A. Gavira, Noel Mesa-Torres, Jose L. Neira, Eduardo Salido, Rogelio J. Palomino-Morales, Miguel Burgos, David Timson, Angel L. Pey

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)3531-3544
Number of pages14
JournalHuman Molecular Genetics
Volume26
Issue number18
DOIs
Publication statusPublished - 6 Jul 2017

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Proteins
Amino Acids
Mutation
Protein Stability
Genetic Suppression
Inborn Genetic Diseases
Flavin-Adenine Dinucleotide
Vertebrates
Mammals
Neoplasms
Binding Sites
Communication
Pharmacology

Bibliographical note

This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Encarnación Medina-Carmona, Julian E. Fuchs, Jose A. Gavira, Noel Mesa-Torres, Jose L. Neira, Eduardo Salido, Rogelio Palomino-Morales, Miguel Burgos, David J. Timson, Angel L. Pey; Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution. Hum Mol Genet 2017 ddx238. doi: 10.1093/hmg/ddx238 is available online at: https://academic.oup.com/hmg/article-abstract/doi/10.1093/hmg/ddx238/3930110/Enhanced-vulnerability-of-human-proteins-towards?redirectedFrom=fulltext, https://doi.org/10.1093/hmg/ddx238

Cite this

Medina-Carmona, E., Fuchs, J. E., Gavira, J. A., Mesa-Torres, N., Neira, J. L., Salido, E., ... Pey, A. L. (2017). Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution. Human Molecular Genetics, 26(18), 3531-3544. https://doi.org/10.1093/hmg/ddx238
Medina-Carmona, Encarnación ; Fuchs, Julian E. ; Gavira, Jose A. ; Mesa-Torres, Noel ; Neira, Jose L. ; Salido, Eduardo ; Palomino-Morales, Rogelio J. ; Burgos, Miguel ; Timson, David ; Pey, Angel L. / Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 18. pp. 3531-3544.
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Medina-Carmona, E, Fuchs, JE, Gavira, JA, Mesa-Torres, N, Neira, JL, Salido, E, Palomino-Morales, RJ, Burgos, M, Timson, D & Pey, AL 2017, 'Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution', Human Molecular Genetics, vol. 26, no. 18, pp. 3531-3544. https://doi.org/10.1093/hmg/ddx238

Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution. / Medina-Carmona, Encarnación; Fuchs, Julian E.; Gavira, Jose A.; Mesa-Torres, Noel; Neira, Jose L.; Salido, Eduardo; Palomino-Morales, Rogelio J.; Burgos, Miguel; Timson, David; Pey, Angel L.

In: Human Molecular Genetics, Vol. 26, No. 18, 06.07.2017, p. 3531-3544.

Research output: Contribution to journalArticle

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AU - Pey, Angel L.

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N2 - 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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Medina-Carmona E, Fuchs JE, Gavira JA, Mesa-Torres N, Neira JL, Salido E et al. Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution. Human Molecular Genetics. 2017 Jul 6;26(18):3531-3544. https://doi.org/10.1093/hmg/ddx238