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Submitted on March 12, 2002
Accepted on October 14, 2002
Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the N-terminal LBD
1 Graduate Group in Biophysics (B.R.H.), Department of Physiology (M.D., H.A.I.), Metabolic Research Unit, Department of Medicine (B.L.W., S.T.C.L., H.N., J.D.B.), Department of Biochemistry and Biophysics (R.J.F.), University of California, San Francisco
* To whom correspondence should be addressed. E-mail: flett{at}msg.ucsf.edu.
Resistance to thyroid hormone (RTH) syndrome is associated with mutations in the human thyroid hormone receptor-
(hTR), many of which show marked reduction in hormone binding. Here, we investigated the structural consequences of two RTH mutants (A234T and R243Q), residing in the flexible N-terminal portion of the ligand binding domain (LBD), which exhibit modestly reduced hormone binding with impaired release of corepressor. X-ray crystallography analyses revealed that these two RTH mutants modulate the position of this flexible region by either altering the movement of helix 1 (A234T) or disrupting a salt bridge (R243Q). The subsequent increased flexibility and mobility in regions after the two sites of mutation coincided with a disorganized LBD. Consistent with this finding, the ability of these mutant N-terminal regions (234-260) to recruit the remaining LBD was decreased in a ligand-dependent helix assembly assay. Collectively, these data suggest that structural information imparted by the flexible segment in the N-terminal LBD is critical for overall stability of the LBD. Thus, these structural analyses provide mechanistic insight into the etiology of resistance to thyroid hormone disease in human TR mutants that exhibit hormone binding with decreased ligand-dependent corepressor release.
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