1b68

File:1b68.gif

spinqualitylabelsall models PDB ID 1b68 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
, resolution 2.00Å
Coordinates:	save as pdb, mmCIF, xml

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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