Linked Life Data

15886199

Source:http://linkedlifedata.com/resource/pubmed/id/15886199

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2005-7-4
pubmed:abstractText
In this study, we investigated how thyroid hormone (3,5',5-triiodo-l-thyronine, T3) inhibits binding of thyroid hormone receptor (TR) homodimers, but not TR-retinoid X receptor heterodimers, to thyroid hormone response elements. Specifically we asked why a small subset of TRbeta mutations that arise in resistance to thyroid hormone syndrome inhibit both T3 binding and formation of TRbeta homodimers on thyroid hormone response elements. We reasoned that these mutations may affect structural elements involved in the coupling of T3 binding to inhibition of TR DNA binding activity. Analysis of TR x-ray structures revealed that each of these resistance to thyroid hormone syndrome mutations affects a cluster of charged amino acids with potential for ionic bond formation between oppositely charged partners. Two clusters (1 and 2) are adjacent to the dimer surface at the junction of helices 10 and 11. Targeted mutagenesis of residues in Cluster 1 (Arg338, Lys342, Asp351, and Asp355) and Cluster 2 (Arg429, Arg383, and Glu311) confirmed that the clusters are required for stable T3 binding and for optimal TR homodimer formation on DNA but also revealed that different arrangements of charged residues are needed for these effects. We propose that the charge clusters are homodimer-specific extensions of the dimer surface and further that T3 binding promotes specific rearrangements of these surfaces that simultaneously block homodimer formation on DNA and stabilize the bound hormone. Our data yield insight into the way that T3 regulates TR DNA binding activity and also highlight hitherto unsuspected T3-dependent conformational changes in the receptor ligand binding domain.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
25665-73
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15886199-Amino Acid Sequence, pubmed-meshheading:15886199-Arginine, pubmed-meshheading:15886199-Aspartic Acid, pubmed-meshheading:15886199-Binding Sites, pubmed-meshheading:15886199-DNA, pubmed-meshheading:15886199-Dimerization, pubmed-meshheading:15886199-Electrochemistry, pubmed-meshheading:15886199-HeLa Cells, pubmed-meshheading:15886199-Humans, pubmed-meshheading:15886199-Ligands, pubmed-meshheading:15886199-Lysine, pubmed-meshheading:15886199-Molecular Sequence Data, pubmed-meshheading:15886199-Mutagenesis, Site-Directed, pubmed-meshheading:15886199-Protein Structure, Tertiary, pubmed-meshheading:15886199-Receptors, Thyroid Hormone, pubmed-meshheading:15886199-Retinoid X Receptors, pubmed-meshheading:15886199-Thyroid Hormone Receptors beta, pubmed-meshheading:15886199-Triiodothyronine
pubmed:year
2005
pubmed:articleTitle
Rearrangements in thyroid hormone receptor charge clusters that stabilize bound 3,5',5-triiodo-L-thyronine and inhibit homodimer formation.
pubmed:affiliation
Diabetes Center and the Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0540, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural