1b68
From Proteopedia
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APOLIPOPROTEIN E4 (APOE4), 22K FRAGMENT
Contents |
Overview
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
Known diseases associated with this structure: Alzheimer disease-2 OMIM:[107741], Hyperlipoproteinemia, type III OMIM:[107741], Macular degeneration, age-related OMIM:[107741], Myocardial infarction susceptibility OMIM:[107741], Sea-blue histiocyte disease OMIM:[107741]
About this Structure
1B68 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Mon Nov 12 16:06:25 2007
