Journal
BIOCHEMICAL JOURNAL
Volume 401, Issue -, Pages 217-226Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20061135
Keywords
complex formation; hypoxia; prolyl hydroxylase domain containing 3 (PHD3); protein degradation; Siah2; ubiquitination
Categories
Funding
- NCI NIH HHS [R01CA111515, R01 CA111515] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA111515] Funding Source: NIH RePORTER
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PHD1-3 (prolyl hydroxylases 1-3) catalyse the hydroxylation of HIF (hypoxia-inducible factor)-alpha subunit that triggers the substrate ubiquitination and subsequent degradation. The RING (really interesting new gene) finger E3 ligase Siah2 preferentially targets PHD3 for degradation. Here, we identify the requirements for such selective targeting. Firstly, PHD3 lacks an N-terminal extension found in PHD1 and PHD2; deletion of this domain from PHD1 and PHD2 renders them susceptible to degradation by Siah2. Secondly, PHD3 can homo- and hetero-multimerize with other PHDs. Consequently, PHD3 is found in high-molecular-mass fractions that were enriched in hypoxia. Interestingly, within the lower-molecular-mass complex, PHD3 exhibits higher specific activity towards hydroxylation of HIF-1 alpha and co-localizes with Siah2, suggesting that Siah2 limits the availability of the more active form of PHD3. These findings provide new insight into the mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2.
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