WSB-1 is a SOCS-box-containing WD-40 protein of unknown function that is induced by Hedgehog signalling in embryonic structures during chicken development. Here we show that WSB-1 is part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2). The WD-40 propeller of WSB-1 recognizes an 18-amino-acid loop in D2 that confers metabolic instability, whereas the SOCS-box domain mediates its interaction with a ubiquitinating catalytic core complex, modelled as Elongin BC-Cul5-Rbx1 (ECS(WSB-1)). In the developing tibial growth plate, Hedgehog-stimulated D2 ubiquitination via ECS(WSB-1) induces parathyroid hormone-related peptide (PTHrP), thereby regulating chondrocyte differentiation. Thus, ECS(WSB-1) mediates a mechanism by which 'systemic' thyroid hormone can effect local control of the Hedgehog-PTHrP negative feedback loop and thus skeletogenesis.
Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder caused by mutations in the MCOLN1 gene, which encodes the 65-kDa protein mucolipin-1. The most common clinical features of patients with MLIV include severe mental retardation, delayed motor milestones, ophthalmologic abnormalities, constitutive achlorhydria, and elevated plasma gastrin levels. Here, we describe the first murine model for MLIV, which accurately replicates the phenotype of patients with MLIV. The Mcoln1(-/-) mice present with numerous dense inclusion bodies in all cell types in brain and particularly in neurons, elevated plasma gastrin, vacuolization in parietal cells, and retinal degeneration. Neurobehavioral assessments, including analysis of gait and clasping, confirm the presence of a neurological defect. Gait deficits progress to complete hind-limb paralysis and death at age ~8 mo. The Mcoln1(-/-) mice are born in Mendelian ratios, and both male and female Mcoln1(-/-) mice are fertile and can breed to produce progeny. The creation of the first murine model for human MLIV provides an excellent system for elucidating disease pathogenesis. In addition, this model provides an invaluable resource for testing treatment strategies and potential therapies aimed at preventing or ameliorating the abnormal lysosomal storage in this devastating neurological disorder.
The three iodothyronine selenodeiodinases catalyze the initiation and termination of thyroid hormone effects in vertebrates. Structural analyses of these proteins have been hindered by their integral membrane nature and the inefficient eukaryotic-specific pathway for selenoprotein synthesis. Hydrophobic cluster analysis used in combination with Position-specific Iterated BLAST reveals that their extramembrane portion belongs to the thioredoxin-fold superfamily for which experimental structure information exists. Moreover, a large deiodinase region imbedded in the thioredoxin fold shares strong similarities with the active site of iduronidase, a member of the clan GH-A-fold of glycoside hydrolases. This model can explain a number of results from previous mutagenesis analyses and permits new verifiable insights into the structural and functional properties of these enzymes.The main secretory product of the thyroid gland is a prohormone thyroxine (T4), which must be monodeiodinated to 3,3Ј,5-triiodothyronine (T3) by removal of an outer ring iodine to permit its binding to nuclear T3 receptors. These ligand-dependent transcription factors regulate genes critical for normal growth, central nervous system development, and energy homeostasis in all vertebrates (1). The specific monodeiodination of T4 in the outer ring is catalyzed by the types 1 or 2 iodothyronine selenodeiodinases (D1 or D2). Termination or prevention of thyroid hormone action is controlled by the inner ring deiodination of T3 or T4, respectively, catalyzed by a third deiodinase, D3. Thus, specific iodothyronine monodeiodinations are critical steps in both the activation and inactivation of thyroid hormones (2). The complex regulation of the activities of these selenocysteine (Sec)-containing enzymes permits modulation of T3 concentrations in specific cells controlling processes diverse as metamorphosis and adaptive thermogenesis. In adult vertebrates, the role of the deiodinases is primarily homeostatic, adjusting T3 production in response to environmental stresses such as iodine deficiency, starvation, or thermal challenges. In addition, the rapid conversion of T4 to T3 by D2 in the central nervous system and pituitary permits accurate monitoring of circulating T4, allowing the feedback regulation of thyroid-stimulating hormone secretion based in part upon circulating pro-hormone (T4) concentrations (2).Although there are important differences among the three deiodinases with respect to their catalytic functions, they have notable similarities. All are integral membrane proteins of 29 -33 kDa and have regions of high similarity in the area surrounding the active center Sec, the critical residue that confers deiodinases with high catalytic activity (3-5). Although there is some structure-function information available, particularly for D1, our understanding of the catalytic mechanisms and three-dimensional conformation of these proteins is limited because of the inability to synthesize large quantities of soluble, catalytically active proteins for cr...
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