1p97: Difference between revisions
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New page: left|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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[[Image:1p97. | [[Image:1p97.jpg|left|200px]]<br /><applet load="1p97" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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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. | ||
==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'' | ||
