Linked Life Data

15084514

Source:http://linkedlifedata.com/resource/pubmed/id/15084514

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2004-6-2
pubmed:abstractText
Hypoxia-inducible factor (HIF)-1alpha, a master regulator of oxygen homeostasis, regulates genes crucial for cell growth and survival. In normoxia, HIF-1alpha is constantly degraded via the ubiquitin-proteasome pathway. The von Hippel-Lindau (VHL) E3 ubiquitin ligase binds HIF-1alpha through specific recognition of hydroxylated Pro-402 or Pro-564, both of which are modified by the oxygen-dependent HIF prolyl hydroxylases (PHDs/HPHs). Despite the identification of a conserved Leu-X-X-Leu-Ala-Pro motif, the molecular requirement of HIF-1alpha for PHDs/HPHs binding remains elusive. Recently, we demonstrated that Leu-574 of human HIF-1alpha--10 residues downstream of Pro-564--is essential for VHL recognition. We show here that the role of Leu-574 is to recruit PHD2/HPH2 for Pro-564 hydroxylation. An antibody specific for hydroxylated Pro-564 has been used to determine the hydroxylation status; mutation or deletion of Leu-574 results in a significant decrease in the ratio of the hydroxylated HIF-1alpha to the total amount. The nine-residue spacing between Pro-564 and Leu-574 is not obligatory for prolyl hydroxylation. Furthermore, mutation of Leu-574 disrupts the binding of PHD2/HPH2, a key prolyl hydroxylase for oxygen-dependent proteolysis of HIF-1alpha. Hence, our findings indicate that Leu-574 is essential for recruiting PHD2/HPH2, thereby providing a molecular basis for modulating HIF-1alpha activity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1530-6860
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1028-30
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed-meshheading:15084514-Amino Acid Sequence, pubmed-meshheading:15084514-Antibodies, pubmed-meshheading:15084514-Cell Line, pubmed-meshheading:15084514-Cell Line, Tumor, pubmed-meshheading:15084514-Humans, pubmed-meshheading:15084514-Hydroxylation, pubmed-meshheading:15084514-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:15084514-Leucine, pubmed-meshheading:15084514-Molecular Sequence Data, pubmed-meshheading:15084514-Mutation, pubmed-meshheading:15084514-Procollagen-Proline Dioxygenase, pubmed-meshheading:15084514-Proline, pubmed-meshheading:15084514-Protein Binding, pubmed-meshheading:15084514-Protein Processing, Post-Translational, pubmed-meshheading:15084514-Thermodynamics, pubmed-meshheading:15084514-Transcription, Genetic, pubmed-meshheading:15084514-Transcription Factors
pubmed:year
2004
pubmed:articleTitle
Leu-574 of human HIF-1alpha is a molecular determinant of prolyl hydroxylation.
pubmed:affiliation
Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
pubmed:publicationType
Journal Article