Structure of an LDLR-RAP Complex Reveals a General Mode for Ligand Recognition by Lipoprotein Receptors
Open accessAbstract
Proteins of the low-density lipoprotein receptor (LDLR) family are remarkable in their ability to bind an extremely diverse range of protein and lipoprotein ligands, yet the basis for ligand recognition is poorly understood. Here, we report the 1.26 A X-ray structure of a complex between a two-module region of the ligand binding domain of the LDLR and the third domain of RAP, an escort protein for LDLR family members. The RAP domain forms a three-helix bundle with two docking sites, one for each LDLR module. The mode of recognition at each site is virtually identical: three conserved, calcium-coordinating acidic residues from each LDLR module encircle a lysine side chain protruding from the second helix of RAP. This metal-dependent mode of electrostatic recognition, together with avidity effects resulting from the use of multiple sites, represents a general binding strategy likely to apply in the binding of other basic ligands to LDLR family proteins.
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None of the LDLa repeats of LRAD3 contains all of the necessary acidic amino acids required for generating an acidic pocket capable of docking lysine side chains from certain LDL receptor family ligands such as RAP.
“None of the LDLa repeats of LRAD3 contains all of the necessary acidic amino acids that are required for generating an acidic pocket capable of docking lysine side chains that protrude from certain LDL receptor family member ligands, such as the receptor associated protein (RAP) (Fisher et al., 2006) (Fig 1D)”
From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Fisher et al., 2006
The three LDLa repeats in LRAD3 ectodomain are homologous to those in LRP and other LDL receptor family members, but none have the three conserved calcium-coordinating acidic residues.
“The three LDLa repeats in the ectodomain are homologous to those found in LRP and other members of the LDL receptor family, but none have the three conserved, calcium-coordinating acidic residues that were found to encircle lysine residues present on LRP ligands (Fisher et al., 2006).”
From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Fisher et al., 2006
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References 34 · Cited by 185
- Authors
- Fisher, C., Beglova, N., & Blacklow, S. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Blacklow, Stephen C.
- ORCID
- Blacklow, Stephen C.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 22
- Issue
- 2
- Pages
- 277-283
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2154521687
- Cited by
- 185
- References
- 34
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 9 · 2023: 12 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 5 · 2016: 11 · 2015: 9 · 2014: 9 · 2013: 9 · 2012: 5
- FWCI
- 13.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (R01-HL61001, R01HL061001)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- LDL receptor, ligand recognition, ligand-binding domain, three-helix bundle, avidity, receptor-ligand complex structure, lipoprotein receptors
- MeSH terms
- Amino Acid Sequence, Apolipoproteins E, Binding Sites, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Protein Binding, Receptors, LDL, Water, Conserved Sequence, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, LDL-Receptor Related Protein-Associated Protein, Static Electricity
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