ReviewStructural and functional aspects of thyroid peroxidase
Section snippets
Gene expression
The human TPO gene spans more than 150 kbp, is located on chromosome 2, and consists of 17 exons and 16 introns [2], [3]. It encodes a 933 amino-acid residue (aa) molecule with a single membrane-spanning region. The closely related human myeloperoxidase (MPO) gene is much smaller (it is only 10 kbp in size) and only the first 735 aa of TPO show 42% similarity with the MPO sequence [4]. TPO has also been found to have a 197-aa extension at the extracellular C-terminal end of the molecule, which
Protein structure
Porcine TPO was first purified after treating thyroid membrane with trypsin and detergent [28], [29], [30], [31], yielding in fine a 90-kDa, enzymatically active, solubilized TPO fragment [32]. Human TPO was subsequently purified from detergent-solubilized thyroid membrane by performing monoclonal antibody (mAb)-assisted affinity chromatography [33], [34], [35], [36], yielding a 105–110-kDa enzymatically active doublet. Glycosylation was not responsible for this molecular heterogeneity [37],
Physiological function
TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues and the coupling of iodotyrosine residues in Tg, resulting in the formation of T3 and T4. The iodination and coupling reactions are not TPO specific because lactoperoxidase [74] and MPO [75] also catalyze these processes. The enzymatic process requires the presence of iodide, H2O2, and Tg. H2O2 is produced at the apical plasma
Immunological structure
In 1985, we identified the thyroid “microsomal antigen” as being TPO [33], [105]. Autoantibodies (aAb) present in the serum of patients with autoimmune thyroid disease (AITD) were found to react with a protein doublet 105–110 kDa in size and to immunoprecipitate TPO [106], [107], [108], [109]. Several patients’ sera against native, denatured, and denatured and reduced TPO recognized numerous B-cell epitopes on the surface of the human TPO molecule [110]. In pioneering studies, we established,
Pathological role
TPO is one of the main thyroid autoantigens. Using a specific, sensitive in-house immunoassay, we found TPO aAb to be present in 88% of all the patients with a thyroid disorder tested [155]. Interestingly, the three main antigens involved in AITD, namely Tg, TPO, and the TSH receptor, are all involved in the production of thyroid hormones. This feature may account for the tissue-specificity of the autoimmune response. These antigens are specific to the thyroid gland, although fatty tissue and
Conclusion
The wide range of TPO data compiled here often raise more questions than they answer. The questions focusing on the 3-D protein structure of TPO and how it is arranged to form a dimer at the membrane surface of thyrocytes still remain to be solved. This gap in our knowledge greatly impedes all efforts to identify the conformational IDR of TPO and its constitutive B- and T-cell epitopes. No data have been published so far on how TPO works with H2O2 to accommodate its two substrates, iodine and
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