Linked Life Data

20460131

Source:http://linkedlifedata.com/resource/pubmed/id/20460131

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-6-14
pubmed:databankReference
pubmed:abstractText
The nuclear protein cyclophilin 33 (Cyp33) is a peptidyl-prolyl cis-trans isomerase that catalyzes cis-trans isomerization of the peptide bond preceding a proline and promotes folding and conformational changes in folded and unfolded proteins. The N-terminal RNA-recognition motif (RRM) domain of Cyp33 has been found to associate with the third plant homeodomain (PHD3) finger of the mixed lineage leukemia (MLL) proto-oncoprotein and a poly(A) RNA sequence. Here, we report a 1.9 A resolution crystal structure of the RRM domain of Cyp33 and describe the molecular mechanism of PHD3 and RNA recognition. The Cyp33 RRM domain folds into a five-stranded antiparallel beta-sheet and two alpha-helices. The RRM domain, but not the catalytic module of Cyp33, binds strongly to PHD3, exhibiting a 2 muM affinity as measured by isothermal titration calorimetry. NMR chemical shift perturbation (CSP) analysis and dynamics data reveal that the beta strands and the beta2-beta3 loop of the RRM domain are involved in the interaction with PHD3. Mutations in the PHD3-binding site or deletions in the beta2-beta3 loop lead to a significantly reduced affinity or abrogation of the interaction. The RNA-binding pocket of the Cyp33 RRM domain, mapped on the basis of NMR CSP and mutagenesis, partially overlaps with the PHD3-binding site, and RNA association is abolished in the presence of MLL PHD3. Full-length Cyp33 acts as a negative regulator of MLL-induced transcription and reduces the expression levels of MLL target genes MEIS1 and HOXA9. Together, these in vitro and in vivo data provide insight into the multiple functions of Cyp33 RRM and suggest a Cyp33-dependent mechanism for regulating the transcriptional activity of MLL.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1089-8638
pubmed:author
pubmed:copyrightInfo
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
400
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
145-54
pubmed:dateRevised
2011-10-31
pubmed:meshHeading
pubmed-meshheading:20460131-Amino Acid Sequence, pubmed-meshheading:20460131-Animals, pubmed-meshheading:20460131-Binding Sites, pubmed-meshheading:20460131-Crystallography, X-Ray, pubmed-meshheading:20460131-Cyclophilins, pubmed-meshheading:20460131-Drosophila Proteins, pubmed-meshheading:20460131-Drosophila melanogaster, pubmed-meshheading:20460131-Gene Expression Regulation, pubmed-meshheading:20460131-Humans, pubmed-meshheading:20460131-Models, Molecular, pubmed-meshheading:20460131-Molecular Sequence Data, pubmed-meshheading:20460131-Mutagenesis, Site-Directed, pubmed-meshheading:20460131-Myeloid-Lymphoid Leukemia Protein, pubmed-meshheading:20460131-Nuclear Magnetic Resonance, Biomolecular, pubmed-meshheading:20460131-Protein Binding, pubmed-meshheading:20460131-Protein Structure, Secondary, pubmed-meshheading:20460131-Protein Structure, Tertiary, pubmed-meshheading:20460131-RNA, pubmed-meshheading:20460131-Sequence Alignment, pubmed-meshheading:20460131-Transcription, Genetic
pubmed:year
2010
pubmed:articleTitle
Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain.
pubmed:affiliation
Department of Pharmacology, University of Colorado Denver School of Medicine, 12801 East 17th Avenue, Aurora, CO 80045, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural