1b68: Difference between revisions
New page: left|200px<br /> <applet load="1b68" size="450" color="white" frame="true" align="right" spinBox="true" caption="1b68, resolution 2.00Å" /> '''APOLIPOPROTEIN E4 (... |
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'''APOLIPOPROTEIN E4 (APOE4), 22K FRAGMENT'''<br /> | '''APOLIPOPROTEIN E4 (APOE4), 22K FRAGMENT'''<br /> | ||
==Overview== | ==Overview== | ||
Apolipoprotein E (apoE) is an important lipid-transport protein in human | Apolipoprotein E (apoE) is an important lipid-transport protein in human plasma and brain. It has three common isoforms (apoE2, apoE3, and apoE4). ApoE is a major genetic risk factor in heart disease and in neurodegenerative disease, including Alzheimer's disease. The interaction of apoE with heparan sulfate proteoglycans plays an important role in lipoprotein remnant uptake and likely in atherogenesis and Alzheimer's disease. Here we report our studies of the interaction of the N-terminal domain of apoE4 (residues 1-191), which contains the major heparin-binding site, with an enzymatically prepared heparin oligosaccharide. Identified by its high affinity for the N-terminal domain of apoE4, this oligosaccharide was determined to be an octasaccharide of the structure DeltaUAp2S(1-->[4)-alpha-D-GlcNpS6S(1-->4)-alpha-L-IdoAp2S(1-->](3)4)-alph a-D-GlcNpS6S by nuclear magnetic resonance spectroscopy, capillary electrophoresis, and polyacrylamide gel electrophoresis. Kinetic analysis of the interaction between the N-terminal apoE4 fragment and immobilized heparin by surface plasmon resonance yielded a K(d) of 150 nM. A similar binding constant (K(d) = 140 nM) was observed for the interaction between immobilized N-terminal apoE4 and the octasaccharide. Isothermal titration calorimetry revealed a K(d) of 75 nM for the interaction of the N-terminal apoE fragment and the octasaccharide with a binding stoichiometry of approximately 1:1. Using previous studies and molecular modeling, we propose a binding site for this octasaccharide in a basic residue-rich region of helix 4 of the N-terminal fragment. From the X-ray crystal structure of the N-terminal apoE4, we predicted that binding of the octasaccharide at this site would result in a change in intrinsic fluorescence. This prediction was confirmed experimentally by an observed increase in fluorescence intensity with octasaccharide binding corresponding to a K(d) of approximately 1 microM. | ||
==Disease== | ==Disease== | ||
Known diseases associated with this structure: Alzheimer disease-2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Hyperlipoproteinemia, type III OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Macular degeneration, age-related OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Myocardial infarction susceptibility OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Sea-blue histiocyte disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]] | Known diseases associated with this structure: Alzheimer disease-2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Hyperlipoproteinemia, type III OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Lipoprotein glomerulopathy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Macular degeneration, age-related OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Myocardial infarction susceptibility OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]], Sea-blue histiocyte disease OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 107741]] | ||
==About this Structure== | ==About this Structure== | ||
1B68 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:// | 1B68 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=1B68 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: vldl]] | [[Category: vldl]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:52:00 2008'' | ||
Revision as of 12:52, 21 February 2008
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APOLIPOPROTEIN E4 (APOE4), 22K FRAGMENT
OverviewOverview
Apolipoprotein E (apoE) is an important lipid-transport protein in human plasma and brain. It has three common isoforms (apoE2, apoE3, and apoE4). ApoE is a major genetic risk factor in heart disease and in neurodegenerative disease, including Alzheimer's disease. The interaction of apoE with heparan sulfate proteoglycans plays an important role in lipoprotein remnant uptake and likely in atherogenesis and Alzheimer's disease. Here we report our studies of the interaction of the N-terminal domain of apoE4 (residues 1-191), which contains the major heparin-binding site, with an enzymatically prepared heparin oligosaccharide. Identified by its high affinity for the N-terminal domain of apoE4, this oligosaccharide was determined to be an octasaccharide of the structure DeltaUAp2S(1-->[4)-alpha-D-GlcNpS6S(1-->4)-alpha-L-IdoAp2S(1-->](3)4)-alph a-D-GlcNpS6S by nuclear magnetic resonance spectroscopy, capillary electrophoresis, and polyacrylamide gel electrophoresis. Kinetic analysis of the interaction between the N-terminal apoE4 fragment and immobilized heparin by surface plasmon resonance yielded a K(d) of 150 nM. A similar binding constant (K(d) = 140 nM) was observed for the interaction between immobilized N-terminal apoE4 and the octasaccharide. Isothermal titration calorimetry revealed a K(d) of 75 nM for the interaction of the N-terminal apoE fragment and the octasaccharide with a binding stoichiometry of approximately 1:1. Using previous studies and molecular modeling, we propose a binding site for this octasaccharide in a basic residue-rich region of helix 4 of the N-terminal fragment. From the X-ray crystal structure of the N-terminal apoE4, we predicted that binding of the octasaccharide at this site would result in a change in intrinsic fluorescence. This prediction was confirmed experimentally by an observed increase in fluorescence intensity with octasaccharide binding corresponding to a K(d) of approximately 1 microM.
DiseaseDisease
Known diseases associated with this structure: Alzheimer disease-2 OMIM:[107741], Hyperlipoproteinemia, type III OMIM:[107741], Lipoprotein glomerulopathy OMIM:[107741], Macular degeneration, age-related OMIM:[107741], Myocardial infarction susceptibility OMIM:[107741], Sea-blue histiocyte disease OMIM:[107741]
About this StructureAbout this Structure
1B68 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Interaction of the N-terminal domain of apolipoprotein E4 with heparin., Dong J, Peters-Libeu CA, Weisgraber KH, Segelke BW, Rupp B, Capila I, Hernaiz MJ, LeBrun LA, Linhardt RJ, Biochemistry. 2001 Mar 6;40(9):2826-34. PMID:11258893
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