1le2
From Proteopedia
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| , resolution 3.0Å | |||||||
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| Gene: | E2 (Homo sapiens) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E
Contents |
Overview
BACKGROUND: Apolipoprotein-E (apo-E), a 34kDa blood plasma protein, plays a key role in directing cholesterol transport via its interaction with the low density lipoprotein (LDL) receptor. The amino-terminal domain of apo-E forms an unusually elongated four-helix bundle arranged such that key basic residues involved in LDL receptor binding form a cluster at the end of one of the helices. A common apo-E variant, apo-E2, corresponding to the single-site substitution Arg158-->Cys, displays minimal LDL receptor binding and is associated with significant changes in plasma cholesterol levels and increased risk of coronary heart disease. Surprisingly, the site of mutation in this variant is physically well removed (> 12A) from the cluster of LDL receptor binding residues. RESULTS: We now report the refined crystal structure of the amino-terminal domain of apo-E2, at a nominal resolution of 3.0A. This structure reveals significant conformational changes relative to the wild-type protein that may account for reduced LDL receptor binding. Removal of the Arg158 side chain directly disrupts a pair of salt bridges, causing a compensatory reorganization of salt bridge partners that dramatically alters the charge surface presented by apo-E to its receptor. CONCLUSIONS: It is proposed that the observed reorganization of surface salt bridges is responsible for the decreased receptor binding by apo-E2. This reorganization, essentially functioning as a mutationally induced electrostatic switch to turn off receptor binding, represents a novel mechanism for the propagation of conformational changes over significant distances.
Disease
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 Structure
1LE2 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein., Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW, Agard DA, Structure. 1994 Aug 15;2(8):713-8. PMID:7994571
Page seeded by OCA on Thu Mar 20 12:29:48 2008
