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Cited by 482Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthProtein Structure and Dynamics

Structure of the LDL Receptor Extracellular Domain at Endosomal pH

Open access
Rudenko, Gabby, Henry, Lisa, Henderson, Keith, Ichtchenko, Konstantin, Brown, Michael S., Goldstein, Joseph L., Deisenhofer, Johann·2002·Science
DOI 10.1126/science.1078124
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Abstract

The low-density lipoprotein receptor mediates cholesterol homeostasis through endocytosis of lipoproteins. It discharges its ligand in the endosome at pH < 6. In the crystal structure at pH = 5.3, the ligand-binding domain (modules R2 to R7) folds back as an arc over the epidermal growth factor precursor homology domain (the modules A, B, β propeller, and C). The modules R4 and R5, which are critical for lipoprotein binding, associate with the β propeller via their calcium-binding loop. We propose a mechanism for lipoprotein release in the endosome whereby the β propeller functions as an alternate substrate for the ligand-binding domain, binding in a calcium-dependent way and promoting lipoprotein release.

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Crossref · 10.1126/science.1078124

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  • LRAD3 lacks the EGF and β-propeller domains found in extracellular portions of LDL receptor family members.

    “LRAD3 also lacks the EGF and β-propeller domains that are found in the extracellular portions of LDL receptor family members which are important for pH-induced uncoupling of ligands within acidic endosomal compartments (Davis et al., 1987; Mikhailenko et al., 1999; Rudenko et al., 2002).”

    From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Rudenko et al., 2002

    The Extracellular Domain at Endosomal pH section describes EGF-like repeats and a β-propeller in LDL-R and says the EGF precursor homology domain is required for ligand release. The Monomer description links that domain to release at acidic pH. Neither passage establishes that LRAD3 lacks these domains, so the LRAD3-specific part of the claim is unsupported by this source. (LLM, conf=0.88)

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Authors
Rudenko, G., Henry, L., Henderson, K., Ichtchenko, K., Brown, M. S., Goldstein, J. L., & Deisenhofer, J.
Affiliations
  • Department of Biochemistry,
  • Howard Hughes Medical Institute (US)
  • Lawrence Berkeley National Laboratory (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
  • Ichtchenko, Konstantin
  • Deisenhofer, Johann
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2002-12-20
Volume
298
Issue
5602
Pages
2353-2358
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1078124
OpenAlex
W1576019382
Cited by
482
References
2
Citations by year
2026: 11 · 2025: 19 · 2024: 14 · 2023: 22 · 2022: 16 · 2021: 22 · 2020: 17 · 2019: 25 · 2018: 16 · 2017: 15 · 2016: 21 · 2015: 15 · 2014: 24 · 2013: 20 · 2012: 14
FWCI
24.50
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • University of North Texas Digital Library (University of North Texas) (submittedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • Lawrence Berkeley National Laboratory
Funders
National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
LDL receptor, extracellular domain, endosomal pH, ligand dissociation, beta-propeller, calcium-binding loop, lipoprotein binding, cholesterol homeostasis, endocytosis, crystal structure
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Calcium, Crystallization, Epidermal Growth Factor, Humans, Hydrogen-Ion Concentration, Ligands, Lipoproteins, LDL, Models, Biological, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Protein Precursors, Receptors, LDL, Endosomes, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Folding, Crystallography, X-Ray, Repetitive Sequences, Amino Acid, Hydrophobic and Hydrophilic Interactions

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