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

This study provides an extensive bioinformatics evaluation of the origin and structural complexity of thyroglobulin (TG). We investigate the structural and evolutionary conservation of TG in Petromyzon marinus (sea lamprey) by reconstructing its complete TG sequence and comparing it to human TG. Using genomic data from NCBI, Uniprot, and Ensembl, we assembled a 2831-amino-acid sequence (TGPM), identifying key TG modules, including 11 TG type 1 modules, three TG type 2 modules, five TG type 3 modules, as well as the linker, hinge, and ChEL domains. Sequence alignment with human TG revealed strong conservation of hormonogenic tyrosines and cysteine residues, underscoring their structural significance in both species. We generated a PDB model for TGPM using the Swiss Model program for homology modeling. The full-length sea lamprey TG was subsequently aligned with full-length human TG through the Matchmaker command in UCSF ChimeraX, revealing a consistent structural overlap across all four regions (I, II, III, IV), highlighting their evolutionary conservation. Additionally, we identified a second sea lamprey TG transcript, TGPM ¹⁷⁴⁶ , which begins with the TG type 1-10 module and extends to the carboxyl terminus, exhibiting high homology with TGPM except in region III.

We also present an evolutionary model proposing that nidogen, a protein containing TG type 1 modules, may have been the precursor to TG. Through genetic rearrangements and duplication events, a proto-TG likely emerged, influenced by environmental factors such as ionizing radiation. Structural modifications led to the loss of nidogen’s globular regions, resulting in a secretory proto-TG containing three TG type 1 modules. Successive duplications expanded the TG structure, ultimately forming TG 11 type 1 modules, closely resembling the ancestral TG in Petromyzon marinus . The final evolutionary phase involved the incorporation 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 confirm that the TG complexation process is fully established in lampreys and has remained virtually unchanged throughout vertebrate evolution.