Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor

Jinsong Yang, Lei Zhang, Paul J A Erbel, Kevin H. Gardner, Kan Ding, Joseph A. Garcia, Richard K. Bruick

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The heterodimeric transcription factor hypoxia-inducible factor (HIF) plays an important role in the progression of a number of processes in which O 2 availability is compromised and, as such, has become an increasingly attractive therapeutic target. Although tremendous progress has been made in recent years in unraveling the mechanisms underlying O 2-dependent regulation of HIF through its O2-dependent degradation domain and C-terminal transactivation domain, our understanding of the contributions of other structural elements, particularly the Per/ARNT/Sim (PAS)-A and PAS-B domains, to the activity of HIF is incomplete. Using insights derived from the recently determined solution structures of the HIF PAS-B domains as a starting point, we have explored the function(s) of the HIF-2α PAS domains via mutational analysis. In contrast to recent models, our data reveal that both PAS domains of the HIF-α subunit are necessary for heterodimer formation but are not required to mediate other HIF functions in which PAS domains have been implicated. Because disruption of individual PAS domains compromise HIF function independent of the mechanism of HIF induction, these data demonstrate the potential utility of targeting these domains for therapeutic applications.

Original languageEnglish (US)
Pages (from-to)36047-36054
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number43
DOIs
StatePublished - Oct 28 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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