Structure of the LDL Receptor Extracellular Domain at Endosomal pH

  title={Structure of the LDL Receptor Extracellular Domain at Endosomal pH},
  author={Gabby Rudenko and Lisa Henry and Keith Henderson and Konstantin Ichtchenko and Michael S. Brown and Joseph L. Goldstein and Johann Deisenhofer},
  pages={2353 - 2358}
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… 
Mechanism of Low Density Lipoprotein (LDL) Release in the Endosome
The temperature and calcium concentration dependence of LR5 stability clearly indicate that under endosomal conditions the unfolded conformation of the repeat is largely dominant, and a new mechanism for LDL release in the endosome is proposed in which calcium depletion and decreased stability at acidic pH drives LR5 unfolding, which triggers LDL release from the receptor.
The low-density lipoprotein receptor: ligands, debates and lore.
The LDL receptor: how acid pulls the trigger.
Structural features of the low-density lipoprotein receptor facilitating ligand binding and release.
How the LDLR uses flexibility and rigidity of linkers between modules to facilitate ligand binding and low-pH ligand release is discussed.
Structure and physiologic function of the low-density lipoprotein receptor.
The focus of the current review is on biochemical and structural studies of the LDLR and its ligands, emphasizing how structural features of the receptor dictate the binding of low-density lipoprotein (LDL) and beta-migrating forms of very low- density lipop protein (beta-VLDL), how the receptor releases bound ligands at low pH, and how the cytoplasmic tail of the HDLR interfaces with the endocytic machinery.
Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor[S]
The studies show that the interface between the ligand binding domain and the EGF-precursor homology domain seen at acidic pH buries residues mediating both LDL binding and release, consistent with an alternative model of LDL-R whereby multiple modules of the extracellular domain interact with LDL at neutral pH.
LDL receptor/lipoprotein recognition: endosomal weakening of ApoB and ApoE binding to the convex face of the LR5 repeat
Endosomal conditions favour dissociation of LDLR/lipoprotein complexes regardless of whether active displacement of bound lipoproteins by the β‐propeller in LDLR takes place, and the multiple ApoE copies in β‐VLDLs, suggest that LDLR chelates lipoproteinins and enhances complex affinity by using more than one LR.
Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor
Domains in both the LDLR and PCSK9 that are not required for binding (or internalization) are essential forPCSK9-mediated degradation of the HDLR.
Role of an intramolecular contact on lipoprotein uptake by the LDL receptor.


Structural independence of ligand-binding modules five and six of the LDL receptor.
Comparison of proton and multidimensional heteronuclear NMR spectra of individual modules to those of the module pair indicates that most of the significant spectroscopic changes lie within the linker region between modules and that little structural interaction occurs between the cores of modules five and six in the 5-6 pair.
Functional domains of the very low density lipoprotein receptor: molecular analysis of ligand binding and acid-dependent ligand dissociation mechanisms.
Results confirm that ligand uncoupling occurs via an allosteric-type mechanism in which pH induced changes in the EGF and/or YWTD repeats alter the ligand binding properties at the amino-terminal portion of the molecule.
Solution structure of the sixth LDL-A module of the LDL receptor.
The NMR solution structure of the sixth LDL-A module (LR6) from the ligand binding domain of the LDLR is presented, indicating that FH mutations both within and distant from the calcium-binding site give rise to protein-folding defects.
Human Low Density Lipoprotein Receptor Fragment
The refolded receptor fragment was homogeneous, as determined by sodium dodecyl sulfate or non-denaturing polyacrylamide gel electrophoresis and isoelectric focusing, and exhibited properties identical to those of the intact native receptor.
Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module
The structure of ligand-binding repeat 5 (LR5) of the LDLR, determined to 1.7 å resolution by X-ray crystallography and presented here, contains a calcium ion coordinated by acidic residues that lie at the carboxy-terminal end of the domain and are conserved among LDL-A modules.
Vesicle-reconstituted Low Density Lipoprotein Receptor
This combined cryoEM-Nanogold labeling study has provided the first low resolution structural images of the reconstituted, full-length bovine LDL receptor.
Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.
The three-dimensional structure of the human LDL receptor has been determined by two-dimensional NMR spectroscopy and shown to consist of a beta-hairpin structure, followed by a series of beta turns, which may represent a structural paradigm both for the other modules in the LDL receptor and for the homologous domains of several other proteins.
Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair
Multiple point mutations of the LDLR that result in the genetic disease familial hypercholesterolemia alter side chains that form conserved packing and hydrogen bonding interactions in the interior and between propeller blades, suggesting a structural requirement for maintaining the integrity of the interdomain interface.
Identification of Amino Acid Residues That Determine pH Dependence of Ligand Binding to the Asialoglycoprotein Receptor during Endocytosis*
Site-directed mutagenesis of the CRD from the major subunit of the asialoglycoprotein receptor has been used to identify residues that are essential for efficient release of ligand at endosomal pH, and sequence comparisons confirm the importance of these residues in conferring appropriate pH dependence in this family of domains.
NMR structure and backbone dynamics of a concatemer of epidermal growth factor homology modules of the human low-density lipoprotein receptor.
The structure and dynamics of EGF-AB contrast with the N-terminal LB modules, which require calcium ions both for folding to form the correct disulfide connectivities and for maintenance of the folded structure, and are connected by highly mobile linking peptides.