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| | {{STRUCTURE_1le4| PDB=1le4 | SCENE= }} | | {{STRUCTURE_1le4| PDB=1le4 | SCENE= }} |
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| - | '''STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E'''
| + | ===STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E=== |
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| - | ==Overview==
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| - | Human apolipoprotein (apo) E4 (arginine at residue 112) preferentially associates with very low density lipoproteins (VLDL), and apoE3 (cysteine at 112) associates with high density lipoproteins. It has been postulated that the amino-terminal domain, which contains residue 112, influences the lipoprotein preference by interacting with the carboxyl-terminal domain, which contains the lipid-binding region. To delineate the region in the carboxyl-terminal domain mediating lipoprotein binding and involved in isoform preference, we produced truncated apoE3 and apoE4 variants (terminating at residues 251, 260, 266, or 272) in Escherichia coli and assessed them for lipoprotein association. This analysis suggested that residues 260-272 contain important determinants for complete lipoprotein association and isoform preferences. To determine whether positive charge at residue 112 was an absolute requirement for the apoE4 VLDL preference, we compared the distributions of rabbit apoE (equivalent to apoE3, with cysteine at a position corresponding to 112), canine apoE (arginine at the corresponding site), and cysteamine-treated rabbit apoE (cysteine converted to a positively charged residue). Surprisingly, all distributed like human apoE3, suggesting that positive charge at a position corresponding to 112 was not directly responsible for the isoform preference and that other residues in the amino-terminal domain were involved. To determine which residues were involved, the structure of the apoE4 22-kDa fragment (the amino-terminal two-thirds of the molecule) was determined to 2.5 A by x-ray crystallography. Compared with the known four-helix bundle structure of apoE3, the only significant differences in the apoE4 structure were that glutamic acid 109 formed a salt bridge with arginine 112 and that the arginine 61 side chain was displaced to a new position. Site-directed mutagenesis of glutamic acid 109 in apoE3 and arginine 61 in apoE4 demonstrated that the position of the arginine 61 side chain in apoE4 was critical in determining apoE4 lipoprotein distribution, suggesting that arginine 61 interacted with the carboxyl-terminal domain to direct binding to VLDL.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_8071364}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 8071364 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_8071364}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Wilson, C.]] | | [[Category: Wilson, C.]] |
| | [[Category: Lipoprotein]] | | [[Category: Lipoprotein]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 23:50:04 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 13:06:44 2008'' |
Revision as of 10:07, 2 July 2008
Template:STRUCTURE 1le4
STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E
Template:ABSTRACT PUBMED 8071364
About this Structure
1LE4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms., Dong LM, Wilson C, Wardell MR, Simmons T, Mahley RW, Weisgraber KH, Agard DA, J Biol Chem. 1994 Sep 2;269(35):22358-65. PMID:8071364
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