Structural Insights into the Iodothyronine Deiodinase 2 Catalytic Core and Deiodinase Catalysis and Dimerization
Holly Towell,
Doreen Braun,
Alexander Brol,
Andrea di Fonzo,
Eddy Rijntjes,
Josef Köhrle,
Ulrich Schweizer,
Clemens Steegborn
Affiliations
Holly Towell
Department of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447 Bayreuth, Germany
Doreen Braun
Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany
Alexander Brol
Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany
Andrea di Fonzo
Department of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447 Bayreuth, Germany
Eddy Rijntjes
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, 10115 Berlin, Germany
Josef Köhrle
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, 10115 Berlin, Germany
Ulrich Schweizer
Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany
Clemens Steegborn
Department of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447 Bayreuth, Germany
Iodothyronine deiodinases (Dio) are selenocysteine-containing membrane enzymes that activate and inactivate the thyroid hormones (TH) through reductive iodide eliminations. The three deiodinase isoforms are homodimers sharing highly conserved amino acid sequences, but they differ in their regioselectivities for the deiodination reaction and regulatory features. We have now solved a crystal structure of the mouse deiodinase 2 (Dio2) catalytic domain. It reveals a high overall similarity to the deiodinase 3 structure, supporting the proposed common mechanism, but also Dio2-specific features, likely mediating its unique properties. Activity studies with an artificially enforced Dio dimer further confirm that dimerization is required for activity and requires both the catalytic core and the enzyme’s N-terminus. Cross-linking studies reveal the catalytic core’s dimerization interface, providing insights into the architecture of the complete, active Dio homodimer.
