1p97
From Proteopedia
(New page: 200px<br /> <applet load="1p97" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p97" /> '''NMR structure of the C-terminal PAS domain ...) |
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'''NMR structure of the C-terminal PAS domain of HIF2a'''<br /> | '''NMR structure of the C-terminal PAS domain of HIF2a'''<br /> | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Erythrocytosis, familial, 4 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603349 603349]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 1P97 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | + | 1P97 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1P97 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: mixed alpha-beta fold]] | [[Category: mixed alpha-beta fold]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:39:19 2008'' |
Revision as of 14:39, 15 February 2008
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NMR structure of the C-terminal PAS domain of HIF2a
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Erythrocytosis, familial, 4 OMIM:[603349]
About this Structure
1P97 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor., Erbel PJ, Card PB, Karakuzu O, Bruick RK, Gardner KH, Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15504-9. Epub 2003 Dec 10. PMID:14668441
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