Linked Life Data

8940298

Source:http://linkedlifedata.com/resource/pubmed/id/8940298

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
1997-1-3
pubmed:abstractText
We previously identified a carboxy-terminal transactivation function termed AF-2 within the last 15 amino acids of the ligand binding domain of the human retinoic acid receptor alpha (hRAR alpha). Truncation of this region abolished transcriptional activity. Here we provide a systematic analysis using alanine scanning mutagenesis of amino acids from Ser405 to Gly419 on a truncated hRAR alpha (delta419) to identify residues within this region that are responsible for transcriptional activity. Whereas mutations in positions 405, 408, 411, and 415-419 have little or no effect on the ability of modified receptors to activate a DR5 response element, mutations in positions 406, 407, 409, 410, and 412-413 modify either the potency or efficacy of all-trans retinoic acid (tRA) -induced gene transcription. Therefore, receptors with mutations in positions 409, 410, 413, and 414 have low transcriptional activity over a wide range of tRA concentrations. Receptors with mutations in positions 406, 407, and 412 exhibit a maximum transcriptional activity similar to wild-type hRAR alpha, but require higher concentrations of tRA. Replacing residues 405-419 on delta419 with the conserved AF-2 domain from the vitamin D3 receptor or the estrogen receptor results in a receptor with wild-type or low transcriptional activity, respectively. A full-length hRAR alpha mutant with an alanine substitution at position 406 (hRAR alpha M406A) binds tRA, but unlike the truncated M406A, which lacks the "F" region, it is not transcriptionally active. Protease mapping experiments detect a consistent difference in the conformation of hRAR alpha M406A compared to wild-type hRAR alpha. These data define amino acids from Ser405 to Gly419 on delta419 that are critical for transcriptional activity and point to the importance of the conformational integrity of receptor domains in maintaining ligand-induced transcriptional activation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0892-6638
pubmed:author
pubmed:issnType
Print
pubmed:volume
10
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1524-31
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
A systematic analysis of the AF-2 domain of human retinoic acid receptor alpha reveals amino acids critical for transcriptional activation and conformational integrity.
pubmed:affiliation
Department of Metabolic Diseases, Hoffmann-LaRoche, Nutley, New Jersey 07110, USA.
pubmed:publicationType
Journal Article