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Etude de l'hétérogenéite et de la maturation de la thyroperoxydase humaine

Abstract : The human thyroperoxidase (TPO) is the main enzyme involved in thyroid hormone synthesis. This type I membrane-bound glycoprotein expressed at the apical surface of thyrocytes catalyzes both the iodination of thyroglobulin and the coupling of some of the iodotyrosyl residues required for the formation of T3 and T4 thyroid hormones.
During its biosynthesis, the hTPO undergoes post-transcriptional mRNA modification by alternative splicing. Three isoforms have been already described: the hTPO1 (full lenght cDNA), the hTPO2 and the hTPO3 in which exons 10 and 16 are respectively spliced out. During my PhD, we identified and quantified by PCR, five novel spliced isoforms: the hTPO4 (- exon 14), the hTPO5 (- exon 8), the hTPO6 (- exons 10,12,13,14 and 16), the hTPO2/4 (- exons 10 and 14) and the hTPO2/3 (- exnos 10 and 16). These new spliced variants code for proteins with different stability, subcellular localization and enzymatic properties. Moreover we also showed that these splicing events increased in benign and malignant thyroid tissues and could be involved in the loss-of-function of thyroid hormones production observed in tumoral thyroid pathologies.
The hTPO undergoes co- and post-traductional modifications. In the endoplasmic reticulum the protein interact with a set of molecular « chaperone » involved in the properly folding and the quality control machinery of proteins, like calnexin (CNX) and calreticulin. We showed that the surexpression of CNX and its thiol oxido-reductase partner Erp57 did not increased the properly folding rate of the hTPO1. Contrary to CNX, we show that BiP, an other folding protein helper, impaired the maturation process and target hTPO for degradation. In the case of hTPO, BiP seems to be a sensor of the protein degradation pathway.
In a final set of experiments, we identified an N-terminal endoproteolytic cleavage of both hTPO purified from human thyroid gland and extracted from CHO cells. The enzyme implicated in the cleavage belong to the subtilisin-like proteases family, implicated in the maturation process of various receptors and surface proteins. As for the human myeloperoxidase, the prosequence of the hTPO acts as an internal molecular chaperone, helping the proper folding process of the protein.
All together, these results enlarged your understanding of mechanisms involved in the maturation of the hTPO and proposed an additional explanation of the heterogeneity of the hTPO expressed in the human thyroid gland.
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https://tel.archives-ouvertes.fr/tel-00310978
Contributor : Valerie Le Fourn <>
Submitted on : Tuesday, August 12, 2008 - 4:03:12 PM
Last modification on : Monday, January 29, 2018 - 5:28:17 PM
Long-term archiving on: : Saturday, November 26, 2016 - 1:27:17 AM

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  • HAL Id : tel-00310978, version 1

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Valerie Le Fourn. Etude de l'hétérogenéite et de la maturation de la thyroperoxydase humaine. Biochimie [q-bio.BM]. Université de la Méditerranée - Aix-Marseille II, 2005. Français. ⟨tel-00310978⟩

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