Linked Life Data

15670167

Source:http://linkedlifedata.com/resource/pubmed/id/15670167

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2005-1-26
pubmed:abstractText
Lack of functional Fragile X mental retardation protein (FMRP) is the primary cause of the Fragile-mental retardation syndrome in humans. In most cases, the disease results from transcriptional silencing of fragile mental retardation gene 1, fmr1, which encodes FMRP. However, a single missense mutation (I304N) in the second KH domain of FMRP gives rise to a particularly severe case of Fragile X syndrome. A Drosophila homolog of FMRP has been identified, Drosophila Fragile X related protein (dFXRP). The corresponding missense mutation in dFXRP, the I307N, has pronounced effects on the in vivo activity of the protein. The effect of the point mutation on the structure and function of FMRP is unclear, and published data are contradictory. No in vitro structural or stability studies have been performed on dFXRP. Here we show that a construct that contains only the tandem KH1-KH2 domains is a stable, well-folded unit suitable for detailed structural and functional characterization. Using this KH1-KH2 construct we explicitly test a hypothesis that has been proposed to explain the effect of the Ile-->Asn mutation: that it causes complete unfolding of the protein. Here we show that the I307N point mutation does not completely unfold the KH domain. The KH1-KH2 construct bearing I307N substitution is stable in isolation and adopts a native-like fold. Thus our data favor alternative explanations for the in vivo observed loss of dFXRP activity associated with I307N mutation: (a) the point mutation might affect intra and/or inter-molecular interactions of dFXRP; or (b) it might impair dFXRP's interactions with its RNA target(s).
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1742-464X
pubmed:author
pubmed:issnType
Print
pubmed:volume
272
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
872-8
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
New insights into Fragile X syndrome. Relating genotype to phenotype at the molecular level.
pubmed:affiliation
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't