Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution
Por:
Medina-Carmona, E, Fuchs, J, Gavira, J, Mesa-Torres, N, Neira, J, Salido, E, Palomino-Morales, R, Burgos, M, Timson, D and Pey, A
Publicada:
15 sep 2017
Resumen:
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.
Filiaciones:
Medina-Carmona, E:
Univ Granada, Dept Phys Chem, Fac Sci, Granada, Spain
Fuchs, J:
Univ Innsbruck, Inst Gen Inorgan & Theoret Chem, Fac Chem & Pharm, Innsbruck, Austria
Boehringer Ingelheim RCV GmbH & Co KG, Dept Med Chem, Vienna, Austria
Gavira, J:
CSIC UGR, IACT, Lab Estudios Cristalog, Granada, Spain
Mesa-Torres, N:
Univ Granada, Dept Phys Chem, Fac Sci, Granada, Spain
:
Univ Miguel Hernandez, Inst Biol Mol & Celular, Avda Ferrocarril S-N, Alicante 03202, Spain
Inst Biocomp & Fis Sistemas Complejos BIFI, Zaragoza 50009, Spain
Salido, E:
Hosp Univ Canarias, Ctr Biomed Res Rare Dis CIBERER, Tenerife, Spain
Palomino-Morales, R:
Univ Granada, Fac Sci, Dept Biochem & Mol Biol 1, Granada, Spain
Univ Granada, Biomed Res Ctr CIBM, Granada, Spain
Burgos, M:
Univ Granada, Biomed Res Ctr CIBM, Granada, Spain
Univ Granada, Fac Sci, Dept Genet, Granada, Spain
Univ Granada, Fac Sci, Inst Biotechnol, Granada, Spain
Timson, D:
Univ Brighton, Sch Pharm & Biomol Sci, Brighton, E Sussex, England
Pey, A:
Univ Granada, Dept Phys Chem, Fac Sci, Granada, Spain
Green Published, Bronze, Green Submitted
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