Consecuencias estructurales y catalíticas de mutaciones en el sitio activo frente a mutaciones distales en la...

Congenital hypothyroidism can result from mutations in human iodotyrosine deiodinase (hIYD), which catalyzes the deiodination of iodotyrosines (I-Tyr), a key step in thyroid hormone synthesis. Three homozygous mutations (R101W, F105-I106L, and I116T) are known causes of hypothyroidism. This computational study reveals that of the two loop I mutations in the flavin-binding domain (R101W and F105-I106L), F105-I106L has a stronger effect, causing greater structural distortion and weaker packing at the dimerization interface. These mutations reduce the binding energy of flavin and I-Tyr, compared to the wild type, due to a complete loss of R101 crown-like phosphate hydrogen bond in R101W and a partial loss of R101 and R279 hydrogen bonds in F105-I106L. In contrast, the distal I116T mutation has a marginal structural effect, but it alters the solvent-accessible surface area, van der Waals packing, and side-chain flexibility, which may explain its delayed clinical onset. Although the I116T mutation is far from the active site, it strengthens flavin and substrate binding via long-range effects. Protein-folding analysis via the Wako-Saitô-Muñoz-Eaton model shows that the wt-hIYD and R101W fold through the C-terminal region, while F105-I106L and I116T alter the folding pathway. Mutation-specific disruptions can impair electron transfer by altering I-Tyr alignment and flavin ring planarity. These findings reveal how hIYD mutations cause structural, energetic, and catalytic defects linked to hypothyroidism.