A Redundant Role of Human Thyroid Peroxidase Propeptide for Cellular, Enzymatic, and Immunological Activity

Godlewska, Marlena; Góra, Monika; Buckle, Ashley M.; Porebski, Benjamin T.; Kemp, E. Helen; Sutton, Brian J.; Czarnocka, Barbara; Banga, J. Paul

doi:10.1089/thy.2013.0127

Cited by 25 publications

(21 citation statements)

References 59 publications

(77 reference statements)

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“…[25b,28] In the mature enzyme,t he N-terminal propeptide sequence involving amino acids 1-108 is cleaved. [29] Mutations which impair TPO production or maturation decrease TH production, thereby causing congenital hypothyroidism. [30] TPO exhibits 47 %sequence similarity with human MPO.…”

Section: Heme-containing Thyroid Peroxidasementioning

confidence: 99%

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

et al. 2016

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Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l-thyroxine (T4) as a prohormone, and 5'-deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments.

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Section: Heme-containing Thyroid Peroxidasementioning

confidence: 99%

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

et al. 2016

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“…TPO’s domain structure, the engineered constructs and structural models are shown in Figure 1. The ΔproTPOe-8His construct lacks a propeptide domain, which has previously been shown to not influence TPO secretion, activity or immunogenicity 17 . Additionally, the expression of only the ectodomain allows ΔproTPOe-8His to be secreted into the media rather than be retained in the membrane.…”

Section: Resultsmentioning

confidence: 99%

“…Native TPO can be isolated and purified from tissue, although the availability of human thyroid tissue is a limiting factor in any preparation of TPO and rarely is enough produced for significant structural characterisation 40 . Additionally, during maturation TPO is trimmed by proteolytic cleavage within its N-terminal propeptide region 17, 41 . This process of proteolysis is at least in some way responsible for the low homogeneity of TPO that is purified from tissue.…”

Section: Discussionmentioning

confidence: 99%

“…An inverse PCR reaction was performed on pcDNA/FRT5/ΔproTPOe/8His plasmid 17 using the following primers: forward 5’-TGATAGTCTAGAGTCGAC-3’ and reverse 5’-GTGGTGGTGGTGGTGGTGGTGGTGAGTCGCCCGAGGGAGCCT-3’ to introduce a C-terminal 8x His tag into the cDNA of the clone. A DpnI digestion was performed on the PCR products followed by a blunt end ligation.…”

Section: Methodsmentioning

confidence: 99%

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Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Williams

Hoke

et al. 2019

Preprint

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25Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of 26 multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as 27 Graves' disease and Hashimoto's thyroiditis. Here we report the biophysical and structural 28 characterisation of two novel TPO constructs containing only the ectodomain of TPO and lacking the 29 propeptide. Both constructs were enzymatically active and able to bind the patient-derived TR1.9 30 autoantibody. Analytical ultra-centrifugation data suggests that TPO can exist as both a monomer 31 and a dimer. Combined with negative stain electron microscopy and molecular dynamics 32 simulations, these data show that TR1.9 autoantibody preferentially binds the TPO monomer, 33 revealing conformational changes that bring together previously disparate residues into a 34 continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody 35 complex, this study provides validated TPO constructs that will facilitate further characterization, 36 and advances our understanding of the structural, functional and antigenic characteristics of TPO, a 37 molecule behind some of the most common autoimmune diseases. 38 39 40 41 48 (Hashimoto's disease) and hyperthyroidism (Grave's disease) 2,3. AITDs are some of the most 49 common autoimmune diseases in the developed world, with Hashimoto's disease being a strong risk 50 factor for thyroid cancer 4. TPO is suspected to be involved in the pathogenesis of Hashimoto's 51 thyroiditis (prevalence 300-2980 cases per 100,000 in the Western world), leading to thyrocyte 52 destruction via CD8+ T-cell infiltration resulting in hypothyroidism 1,3,5. This incidence rate can be 53 compared to other autoimmune diseases -for example type 1 diabetes, which has an incidence in 54 the developed world of 310-570 cases per 100,000 patients -demonstrating the immense disease 55 burden caused by AITDs 5. The pathogeneses that underlies these autoimmune diseases is complex, 56 however the lack of any tertiary or quaternary structure of TPO complicates matters. The absence of 57 a structure in which to understand binding of anti-TPO antibodies, which are prevalent almost 58 ubiquitously (>95%) in cases of destructive thyroiditis, complicates the understanding of the 59 pathogenesis and nature of the disease. The precise mechanism by which these antibodies cause 60 damage is uncertain 2. Additionally, in some cases AITDs can occur without these autoantibodies 61 being present, and transplacental passage of anti-TPO antibodies does not necessarily cause thyroid 62 damage in the offspring 3,6,7. Despite this, transplacental passage of these autoantibodies can 63 potentially have cognitive effects on the child. In addition, antibodies to thyroglobulin (Tg) and 64 thyroid stimulating hormone receptor have been identified in both conditions, indicating that there 65 may be multiple antigens in AITD pathogenesis 2. 66TPO is a member of the animal heme peroxidase family, which also includes myelope...

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“…This may result in a lack of recognition/identification of some of them by the different methods [26,27].…”

Section: Discussionmentioning

confidence: 99%

Immunoassay of thyroid peroxidase autoantibodies: diagnostic performance in automated third generation methods. A multicentre evaluation

D’Aurizio

Tozzoli

Villalta

et al. 2015

Clinical Chemistry and Laboratory Medicine (CCLM)

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A Redundant Role of Human Thyroid Peroxidase Propeptide for Cellular, Enzymatic, and Immunological Activity

Cited by 25 publications

References 59 publications

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Immunoassay of thyroid peroxidase autoantibodies: diagnostic performance in automated third generation methods. A multicentre evaluation

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