Publication Date:
2002-05-11
Description:
The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Min, Jung-Hyun -- Yang, Haifeng -- Ivan, Mircea -- Gertler, Frank -- Kaelin, William G Jr -- Pavletich, Nikola P -- New York, N.Y. -- Science. 2002 Jun 7;296(5574):1886-9. Epub 2002 May 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellular Biochemistry and Biophysics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12004076" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Binding Sites
;
Crystallography, X-Ray
;
Humans
;
Hydrogen Bonding
;
Hydrophobic and Hydrophilic Interactions
;
Hydroxylation
;
Hydroxyproline/*metabolism
;
Hypoxia-Inducible Factor 1, alpha Subunit
;
Ligases/*chemistry/genetics/metabolism
;
Macromolecular Substances
;
Mice
;
Models, Molecular
;
Molecular Sequence Data
;
Mutation
;
Protein Conformation
;
Protein Structure, Secondary
;
Protein Structure, Tertiary
;
Signal Transduction
;
Transcription Factors/*chemistry/metabolism
;
*Tumor Suppressor Proteins
;
*Ubiquitin-Protein Ligases
;
Von Hippel-Lindau Tumor Suppressor Protein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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