Crystal structure of mouse mu-crystallin complexed with NADPH and the T3 thyroid hormone.

Abstract : Mu-crystallin (CRYM), first described as a structural component of the eye lens in marsupials, has been characterized as an NADPH-dependent cytosolic T3 thyroid hormone (triiodothyronine) binding protein. More recently, CRYM has also been associated with ketimine reductase activity. Here, we report three crystal structures: mouse CRYM (mCRYM) in its apo form, in a form complexed with NADPH, and in a form with both NADPH and triiodothyronine bound. Comparison of the apo and NADPH forms reveals a rearrangement of the protein upon NADPH binding that reduces the degrees of freedom of several residues and traps the conformation of the binding pocket in a more T3 competent state. These findings are in agreement with the cooperative mechanism identified using isothermal titration calorimetry. Our structure with T3 reveals for the first time the location of the hormone binding site and shows its detailed interactions. T3 binding involves mainly hydrophobic interactions. Only five residues, either directly or through bridging water molecules, are hydrogen bonded to the hormone. Using in silico docking analysis, a series of ring-containing hydrophobic molecules were identified as potential mCRYM ligands, suggesting that the specificity for the recognition of the hydrophobic part of the hormone might be low. This is in agreement with the ketimine reductase activity that has been identified for ovine CRYM, as it demonstrates how a protein known as a thyroid hormone transporter can accommodate the ringed molecules required for its ketimine reductase activity. In the light of our results, a putative role of CRYM in thyroid hormone metabolism is also discussed. CRYM and CRYM bind by x-ray crystallography (View interaction).
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Article dans une revue
FEBS Journal, Wiley, 2014, 281 (6), pp.1598-612
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http://hal.univ-grenoble-alpes.fr/hal-01130670
Contributeur : Frank Thomas <>
Soumis le : jeudi 12 mars 2015 - 10:46:34
Dernière modification le : lundi 19 février 2018 - 14:34:04

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  • HAL Id : hal-01130670, version 1
  • PUBMED : 24467707

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Franck Borel, Isma Hachi, Andres Palencia, Marie-Claude Gaillard, Jean-Luc Ferrer. Crystal structure of mouse mu-crystallin complexed with NADPH and the T3 thyroid hormone.. FEBS Journal, Wiley, 2014, 281 (6), pp.1598-612. 〈hal-01130670〉

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