| Structural highlights
Disease
[LDLR_HUMAN] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:143890]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [:][32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]
Function
[LDLR_HUMAN] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
Publication Abstract from PubMed
The Low Density Lipoprotein Receptor (LDLR), the primary receptor for cholesterol uptake, binds ligands through its seven LDL-A modules (LAs). We present NMR and ligand binding measurements on the fourth and fifth modules of the LDLR (LA45), the modules critical for ApoE binding, at physiological pH. Unlike LA5 and all other modules in LDLR, LA4 has a very weak calcium affinity, which probably plays a critical role in endosomal ligand release. The NMR solution structure of each module in the LA45 pair only showed minor differences compared to the analogous domains in previously solved crystal structures. The 12 residue linker connecting the modules, though slightly structured through an interaction with LA4, is highly flexible. Although no inter-module NOEs were detected, chemical shift perturbations and backbone dynamics suggest crosstalk between the two modules. The ligand affinity of both modules is enhanced when the two are linked. LA4 is more flexible than LA5 and remains so even in the module pair, which likely relates to its weaker calcium-binding affinity.
Structure, dynamics and binding of the LA45 module pair of the Low Density Lipoprotein Receptor suggest an important role for LA4 in ligand release.,Guttman M, Komives EA Biochemistry. 2011 Nov 17. PMID:22091758[44]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Guttman M, Komives EA. Structure, dynamics and binding of the LA45 module pair of the Low Density Lipoprotein Receptor suggest an important role for LA4 in ligand release. Biochemistry. 2011 Nov 17. PMID:22091758 doi:10.1021/bi2014486
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