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Reenacting the Birth of a Function: Functional Divergence of HIUases and Transthyretins as Inferred by Evolutionary and Biophysical Studies
Journal of Molecular Evolution  (IF2.395),  Pub Date : 2021-05-06, DOI: 10.1007/s00239-021-10010-8
Lucas Carrijo de Oliveira, Mariana Amalia Figueiredo Costa, Natan Gonçalves Pedersolli, Fernanda Aparecida Heleno Batista, Ana Carolina Migliorini Figueira, Rafaela Salgado Ferreira, Ronaldo Alves Pinto Nagem, Laila Alves Nahum, Lucas Bleicher

Transthyretin was discovered in the 1940s, named after its ability to bind thyroid hormones and retinol. In the genomic era, transthyretins were found to be part of a larger family with homologs of no obvious function, then called transthyretin-related proteins. Thus, it was proposed that the transthyretin gene could be the result of gene duplication of an ancestral of this newly identified homolog, later found out to be an enzyme involved in uric acid degradation, then named HIUase (5-hydroxy-isourate hydrolase). Here, we sought to re-enact the evolutionary history of this protein family by reconstructing, from a phylogeny inferred from 123 vertebrate sequences, three ancestors corresponding to key moments in their evolution—before duplication; the common transthyretin ancestor after gene duplication and the common ancestor of Eutheria transthyretins. Experimental and computational characterization showed the reconstructed ancestor before duplication was unable to bind thyroxine and likely presented the modern HIUase reaction mechanism, while the substitutions after duplication prevented that activity and were enough to provide stable thyroxine binding, as confirmed by calorimetry and x-ray diffraction. The Eutheria transthyretin ancestor was less prone to characterization, but limited data suggested thyroxine binding as expected. Sequence/structure analysis suggests an early ability to bind the Retinol Binding Protein. We solved the X-ray structures from the two first ancestors, the first at 1.46 resolution, the second at 1.55 resolution with well-defined electron density for thyroxine, providing a useful tool for the understanding of structural adaptation from enzyme to hormone distributor.