Abstract
Iodothyronine deiodinases (Dios) are important selenoproteins that control the concentration of the active thyroid hormone (TH) triiodothyronine through regioselective deiodination. The X-ray structure of a truncated monomer of Type III Dio (Dio3), which deiodinates TH inner rings through a selenocysteine (Sec) residue, revealed a thioredoxin-fold catalytic domain supplemented with an unstructured Ω-loop. Loop dynamics are driven by interactions of the conserved Trp207 with solvent in multi-microsecond molecular dynamics simulations of the Dio3 thioredoxin(Trx)-fold domain. Hydrogen bonding interactions of Glu200 with residues conserved across the Dio family anchor the loop’s N-terminus to the active site Ser-Cys-Thr-Sec sequence. A key long-lived loop conformation coincides with the opening of a cryptic pocket that accommodates thyroxine (T4) through an I⋯Se halogen bond to Sec170 and the amino acid group with a polar cleft. The Dio3-T4 complex is stabilized by an I⋯O halogen bond between an outer ring iodine and Asp211, consistent with Dio3 selectivity for inner ring deiodination. Non-conservation of residues, such as Asp211, in other Dio types in the flexible portion of the loop sequence suggests a mechanism for regioselectivity through Dio type-specific loop conformations. Cys168 is proposed to attack the selenenyl iodide intermediate to regenerate Dio3 based upon structural comparison with related Trx-fold proteins.
Highlights
Iodothyronine deiodinase (Dio) membrane selenoproteins regulate thyroid hormone (TH) activity through regioselective deiodination (Fig. 1a)[1,2,3,4,5,6,7,8,9,10]
XB interactions differ in strength for inner and outer-ring iodines when calculated by density functional theory (DFT)[24,27], the regioselectivity of deiodination (IRD vs outer ring deiodination (ORD)) must be controlled by interactions between the substrate and active site residues[24]
These results are consistent with normal mode analysis[31] of the X-ray structure which indicates that the motion of the active site SCTU sequence and the Ω-loop are slightly correlated (See Supporting Information)
Summary
Iodothyronine deiodinase (Dio) membrane selenoproteins regulate thyroid hormone (TH) activity through regioselective deiodination (Fig. 1a)[1,2,3,4,5,6,7,8,9,10]. Ω-loops, first described by Fetrow (Lezsczynski) et al, are irregular secondary protein structural m otifs[28,29,30] that lack repeating backbone dihedral or hydrogen bonding p atterns[28] These features are commonly found on the exterior of proteins, suggesting a role in substrate binding, catalytic activity, Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA. While the Trx-fold and the N-terminal AHxxDGW sequence of the β2αD loop is conserved across the Dio family, the length and sequence of the Ω-loop varies significantly while maintaining high similarity within types (Fig. 1d) suggesting a potential contribution to Dio regioselectivity Of this sequence, His[202] (corresponding to His[162] for Dio[2] and His[158] for Dio[1] in Mus musculus) was proposed to bind the 4′-phenol of T Hs14, but the role of other conserved residues have not been established. Extending this understanding of the role of the Ω-loop and XB interactions to Dio3-T4 binding to both the mechanism and selectivity could lead to development of targeted treatments for thyroid hormone-related disease
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