Evolution of thyroglobulin: an integrated view of its origin and complexity from a structural perspective.

This study presents a comprehensive bioinformatics analysis of the origin and structural complexity of thyroglobulin (TG). We examine the structural and evolutionary conservation of TG in Petromyzon marinus (sea lamprey) by reconstructing its complete TG sequence. Based on genomic data, we assembled a 2,831-amino-acid sequence (TGPM), identifying key TG domains and generating a homology-based PDB model. Additionally, we detected a second TG transcript in sea lamprey, designated TGPM1746 Comparative analysis across 38 representative vertebrate species--including mammals, birds, reptiles, amphibians, ray-finned fishes, and jawless vertebrates--reveals that all TG domains are conserved throughout vertebrate evolution. Despite substantial divergence in overall amino acid sequences, tyrosine residues and cysteines--both essential for TG function--remain highly conserved. TG emerges as a structurally complex, multidomain protein featuring a conserved disordered segment at its C-terminus. This region includes the terminal portion of the ChEL domain and the hormonogenic site responsible for triiodothyronine (T3) synthesis, likely contributing to the conformational flexibility required for hormone production. We further propose an evolutionary model in which a nidogen-like precursor--defined by the presence of TG type 1 modules--may have acted as the ancestral source of this essential repetitive motif within TG structure. Through genetic rearrangements and duplication events, a proto-TG likely arose, potentially shaped by environmental pressures such as ionizing radiation. Successive duplications expanded the TG architecture, culminating in the formation of 11 TG type 1 modules. The final evolutionary stage involved the integration of TG type 3 and TG type 2 modules, followed by the fusion of the ChEL domain, which enhanced TG secretion and thyroid hormone biosynthesis. Our findings demonstrate that the TG complexation process is fully established in lampreys and has remained remarkably conserved across vertebrate evolution.