Linked Life Data

15100232

Source:http://linkedlifedata.com/resource/pubmed/id/15100232

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
29
pubmed:dateCreated
2004-7-12
pubmed:abstractText
The low density lipoprotein (LDL) receptor is a modular protein involved in the endocytosis of cholesterol-rich lipoproteins from the circulation. Mutations to the receptor result in familial hypercholesterolemia, and over 60 of these occur in the calcium-binding epidermal growth factor-like domain pair. Two selected mutations in this region (G322S and R329P) were introduced into the domain pair and analyzed by in vitro refolding. Both exhibited differing levels of protein misfolding with R329P being the most pronounced. Solution NMR studies of the mutant domain pairs after purification established that a fraction of protein maintains a native-like fold and that this fraction contains two intact calcium-binding sites. An in vivo analysis of intact receptors containing these binding sites showed significantly reduced cell-surface expression compared with the native LDL receptor levels, again with R329P showing the most severe decrease. The sum of these results suggests that either local changes in structure or domain misfolding may be associated with the mutations. There is also the possibility that the misfolding of the calcium-binding epidermal growth factor-like pair region is propagated to other regions of the intact receptor, resulting in more global defects. Surprisingly, for both mutants, those full-length receptors that fold and reach the cell surface retain the ability to bind LDL and release the ligand upon exposure to low pH. This analysis provides significant insight into the protein defect resulting from each of the two mutations and allows their classification to be 2B (partially transport-defective). The results also highlight a range of misfolding defects that may be associated with familial hypercholesterolemia and may enable the prediction of the consequences of homologous disease-causing mutations to other proteins.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
30611-21
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15100232-Binding Sites, pubmed-meshheading:15100232-Blotting, Western, pubmed-meshheading:15100232-Calcium, pubmed-meshheading:15100232-Cell Line, pubmed-meshheading:15100232-Cell Membrane, pubmed-meshheading:15100232-Chelating Agents, pubmed-meshheading:15100232-Chromatography, High Pressure Liquid, pubmed-meshheading:15100232-Epidermal Growth Factor, pubmed-meshheading:15100232-Flow Cytometry, pubmed-meshheading:15100232-Humans, pubmed-meshheading:15100232-Hydrogen-Ion Concentration, pubmed-meshheading:15100232-Hypercholesterolemia, pubmed-meshheading:15100232-Kinetics, pubmed-meshheading:15100232-Ligands, pubmed-meshheading:15100232-Magnetic Resonance Spectroscopy, pubmed-meshheading:15100232-Models, Molecular, pubmed-meshheading:15100232-Mutation, pubmed-meshheading:15100232-Plasmids, pubmed-meshheading:15100232-Protein Binding, pubmed-meshheading:15100232-Protein Folding, pubmed-meshheading:15100232-Protein Structure, Secondary, pubmed-meshheading:15100232-Protein Structure, Tertiary, pubmed-meshheading:15100232-Receptors, LDL, pubmed-meshheading:15100232-Time Factors
pubmed:year
2004
pubmed:articleTitle
Global defects in the expression and function of the low density lipoprotein receptor (LDLR) associated with two familial hypercholesterolemia mutations resulting in misfolding of the LDLR epidermal growth factor-AB pair.
pubmed:affiliation
Department of Biochemistry, Division of Structural Biology, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't