Phylogenetic analysis of the human thyroglobulin regions

Abstract

Thyroglobulin is a large protein present in all vertebrates. It is synthesized in the thyrocytes and exported to lumen of the thyroid follicle, where its tyrosine residues are iodinated . The iodinated thyroglobulin is reintegrated into the cell and processed (cleaved to free its two extremities) for thyroid hormone synthesis. Thyroglobulin sequence analysis has identified four regions of the molecule: Tg1, Tg2, Tg3 and ChEL. Structural abnormalities and mutations result in different pathological consequences, depending on the thyroglobulin region affected. We carried out a bioinformatic analysis of thyroglobulin, determining the origin and the function of each region. Our results suggest that the Tg1 region acts as a binding protein on the apical membrane, the Tg2 region is involved in protein adhesion and the Tg3 region is involved in determining the three-dimensional structure of the protein. The ChEL domain is involved in thyroglobulin transport, dimerization and adhesion. The presence of repetitive domains in the Tg1, Tg2 and Tg3 regions suggests that these domains may have arisen through duplication.

Insights into the posttranslational structural heterogeneity of thyroglobulin and its role in the development, diagnosis, and management of benign and malignant thyroid diseases

“…Tg is known to being enhanced with species development. Recent comparative phylogenetic analyses of Tg from echinoderms, amphibians, zebrafish, and vertebrates provide evidence of the continued evolution of this protein (14).…”

“…The first 19 residues of the N-terminal end constitute the signal peptide, which directs the pre-polypeptide during posttranslational processing and secretion into the Golgi complex (9,14) (Figure 1).…”

“…By forming disulfide bonds between monomers, these residues increase molecular stability and resistance to proteolysis (14). These domain types are: type 1, composed of approximately 50 residues which repeat 10 times between amino acids 1 and 1200; type 2, composed of 14-17 residues that repeat three times between positions 1436 and 1483; and type 3, which is composed of two subtypes (A and B) that repeat five times between positions 1583 and 2170 (16).…”

“…These domain types are: type 1, composed of approximately 50 residues which repeat 10 times between amino acids 1 and 1200; type 2, composed of 14-17 residues that repeat three times between positions 1436 and 1483; and type 3, which is composed of two subtypes (A and B) that repeat five times between positions 1583 and 2170 (16). It has been speculated that each of these regions has a different function, with region 1 controlling Tg binding to other proteins; region 2 controlling cell adhesion; and region 3 playing a structural role (14).…”

Thyroglobulin Represents a Novel Molecular Architecture of Vertebrates

“…As a consequence, it remains unknown how the TH precursor protein emerged during evolution. Based on biochemical characterization, there have been a few reports of possible Tg orthologs in invertebrate chordates (16), but these assignments have remained controversial (17). Surprisingly, no complete Tg has yet been characterized in Xenopus or zebrafish, two major model systems that have been used to decipher the role of THs in physiology and development (8,18).…”