1P97

NMR structure of the C-terminal PAS domain of HIF2a

Summary for 1P97

• Entry DOI: 10.2210/pdb1p97/pdb
• Descriptor: Endothelial PAS domain protein 1 (1 entity in total)
• Functional Keywords: mixed alpha-beta fold, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (Potential): Q99814
• Total number of polymer chains: 1
• Total formula weight: 13192.98

Authors

Erbel, P.J.,Card, P.B.,Karakuzu, O.,Bruick, R.K.,Gardner, K.H. (deposition date: 2003-05-09, release date: 2004-01-13, Last modification date: 2024-05-22)

Primary citation

Erbel, P.J.,Card, P.B.,Karakuzu, O.,Bruick, R.K.,Gardner, K.H.
Structural basis for PAS domain heterodimerization in the basic helix-loop-helix-PAS transcription factor hypoxia-inducible factor.
Proc.Natl.Acad.Sci.USA, 100:15504-15509, 2003

PubMed Abstract: Biological responses to oxygen availability play important roles in development, physiological homeostasis, and many disease processes. In mammalian cells, this adaptation is mediated in part by a conserved pathway centered on the hypoxia-inducible factor (HIF). HIF is a heterodimeric protein complex composed of two members of the basic helix-loop-helix Per-ARNT-Sim (PAS) (ARNT, aryl hydrocarbon receptor nuclear translocator) domain family of transcriptional activators, HIFalpha and ARNT. Although this complex involves protein-protein interactions mediated by basic helix-loop-helix and PAS domains in both proteins, the role played by the PAS domains is poorly understood. To address this issue, we have studied the structure and interactions of the C-terminal PAS domain of human HIF-2alpha by NMR spectroscopy. We demonstrate that HIF-2alpha PAS-B binds the analogous ARNT domain in vitro, showing that residues involved in this interaction are located on the solvent-exposed side of the HIF-2alpha central beta-sheet. Mutating residues at this surface not only disrupts the interaction between isolated PAS domains in vitro but also interferes with the ability of full-length HIF to respond to hypoxia in living cells. Extending our findings to other PAS domains, we find that this beta-sheet interface is widely used for both intra- and intermolecular interactions, suggesting a basis of specificity and regulation of many types of PAS-containing signaling proteins.

PubMed: 14668441
DOI: 10.1073/pnas.2533374100

Experimental method

SOLUTION NMR