Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
27175606
DOI
10.1016/j.atherosclerosis.2016.04.022
PII: S0021-9150(16)30153-8
Knihovny.cz E-resources
- Keywords
- Endoplasmic reticulum, Familial hypercholesterolemia, Fluorescence microscopy, LDL, Modeling, Mutations, Signal sequence,
- MeSH
- Arginine chemistry MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Endoplasmic Reticulum metabolism MeSH
- Glycine chemistry MeSH
- Heterozygote MeSH
- Hyperlipoproteinemia Type II blood genetics MeSH
- Microscopy, Confocal MeSH
- Cricetinae MeSH
- Receptors, LDL genetics metabolism MeSH
- Leucine chemistry MeSH
- Humans MeSH
- Mutation MeSH
- Proline chemistry MeSH
- Protein Sorting Signals genetics MeSH
- Pedigree MeSH
- Protein Folding MeSH
- Protein Structure, Secondary MeSH
- Animals MeSH
- Check Tag
- Cricetinae MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Arginine MeSH
- Glycine MeSH
- Receptors, LDL MeSH
- LDLR protein, human MeSH Browser
- Leucine MeSH
- Proline MeSH
- Protein Sorting Signals MeSH
The low density lipoprotein receptor (LDLR) is a transmembrane protein that plays a key role in cholesterol metabolism. It contains 860 amino acids including a 21 amino acid long signal sequence, which directs the protein into the endoplasmic reticulum. Mutations in the LDLR gene lead to cholesterol accumulation in the plasma and results in familial hypercholesterolemia (FH). Knowledge of the impact of a mutation on the LDLR protein structure and function is very important for the diagnosis and management of FH. Unfortunately, for a large proportion of mutations this information is still missing. In this study, we focused on the LDLR signal sequence and carried out functional and in silico analyses of two sequence changes, p.(Gly20Arg) and p.(Leu15Pro), localized in this part of the LDLR. Our results revealed that the p.(Gly20Arg) change, previously described as disease causing, has no detrimental effect on protein expression or LDL particle binding. In silico analysis supports this observation, showing that both the wt and p.(Gly20Arg) signal sequences adopt an expected α-helix structure. In contrast, the mutation p.(Leu15Pro) is not associated with functional protein expression and exhibits a structure with disrupted a α-helical arrangement in the signal sequence, which most likely affects protein folding in the endoplasmic reticulum.
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