ArticleThe Journal of biological chemistry2008
The epidermal growth factor homology domain of the LDL receptor drives lipoprotein release through an allosteric mechanism involving H190, H562, and H586.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Role of Next-Generation Sequencing in Diagnosis of Familial Hypercholesterolemia in Serbia.Diagnostics (Basel, Switzerland) · 2025Article
- CRISPR-Cas9-guided amplification-free genomic diagnosis for familial hypercholesterolemia using nanopore sequencing.PloS one · 2024Article
- Endocrine Regulation of Microvascular Receptor-Mediated Transcytosis and Its Therapeutic Opportunities: Insights by PCSK9-Mediated Regulation.Pharmaceutics · 2023Review
- Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR.Scientific reports · 2020Article
- Identification of roles for H264, H306, H439, and H635 in acid-dependent lipoprotein release by the LDL receptor.Journal of lipid research · 2017Article
- Structural changes induced by acidic pH in human apolipoprotein B-100.Scientific reports · 2016Article
- Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia.Human molecular genetics · 2016Article
- Article
- The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation.Journal of lipid research · 2013Article
- S-nitrosylation of ARH is required for LDL uptake by the LDL receptor.Journal of lipid research · 2013Article
- Quantitative fluorescence imaging reveals point of release for lipoproteins during LDLR-dependent uptake.Journal of lipid research · 2013Article
- Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.EMBO reports · 2011Article
- Role of an intramolecular contact on lipoprotein uptake by the LDL receptor.Biochimica et biophysica acta · 2011Article
- Apolipoprotein E: from lipid transport to neurobiology.Progress in lipid research · 2011Review
- Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor.Journal of lipid research · 2010Article
- Model of human low-density lipoprotein and bound receptor based on cryoEM.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Low pH-triggered beta-propeller switch of the low-density lipoprotein receptor assists rhinovirus infection.Journal of virology · 2009Article
- The role of calcium in lipoprotein release by the low-density lipoprotein receptor.Biochemistry · 2009Article
- Receptor-associated protein (RAP) has two high-affinity binding sites for the low-density lipoprotein receptor-related protein (LRP): consequences for the chaperone functions of RAP.The Biochemical journal · 2009Article
- Domain swapping reveals that low density lipoprotein (LDL) type A repeat order affects ligand binding to the LDL receptor.The Journal of biological chemistry · 2009Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The low density lipoprotein (LDL) receptor (LDLR) mediates efficient endocytosis of VLDL, VLDL remnants, and LDL. As part of the endocytic process, the LDLR releases lipoproteins in endosomes. The release process correlates with an acid-dependent conformational change in the receptor from an extended, "open" state to a compact, "closed" state. The closed state has an intramolecular contact involving H190, H562, and H586. The current model for lipoprotein release holds that protonation of these histidines drives the conformational change that is associated with release. We tested the roles of H190, H562, and H586 on LDLR conformation and on lipoprotein binding, uptake, and release using variants in which the three histidines were replaced with alanine (AAA variant) or in which the histidines were replaced with charged residues that can form ionic contacts at neutral pH (DRK variant). Contrary to expectation, both the AAA and the DRK variants exhibited normal acid-dependent transitions from open to closed conformations. Despite this similarity, both the AAA and DRK mutations modulated lipoprotein release, indicating that H190, H562, and H586 act subsequent to the conformational transition. These observations also suggest that the intramolecular contact does not drive release through a competitive mechanism. In support of this possibility, mutagenesis experiments showed that beta-VLDL binding was inhibited by mutations at D203 and E208, which are exposed in the closed conformation of the LDLR. We propose that H190, H562, and H586 are part of an allosteric mechanism that drives lipoprotein release.
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