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#LDL receptor

3 public questions tagged with this topic.

Protein Sorting and Trafficking

Which adapter protein interacts with the NPXY motif of LDL receptors?

LDL receptor internalization requires highly specific recognition cytosolic tail by endocytic co-adaptors bridging to clathrin lattice enhancing efficiency. Tail 50 amino acids contains conserved FXNPXY motif positions 802-807 forming tight beta-turn favored aromatic phenylalanine tyrosine. PTB domains autosomal recessive hypercholesterolemia protein ARH LDLRAP1 and Dab2 Disabled-2 liver recognize NPXY tyrosine hydrophobic pocket interacting also basic residues upstream motif. Adaptors contain additional trafficking domains: clathrin box binding heavy chain terminal domain, AP2 beta2 appendage binding DxF sites, N-terminal PIP2-binding FERM-like domain anchoring plasma membrane. Thus co-adaptor physically links receptor tail simultaneously phosphoinositide clathrin AP2 ensuring rapid clustering coated pits half-life two minutes. Direct interaction NPXY to AP2 mu2 very weak; co-adaptor amplifies specificity. AP1 TGN via gamma adaptin, AP3 lysosome-related organelles membranes. Mutation Tyr807Cys causing FH class 4 prevents ARH binding receptors remain diffusely surface normal LDL binding but severely reduced uptake leading hypercholesterolemia reflecting sorting defect not binding defect, highlighting co-adaptor necessity and pathway logic.

Ref: He et al., Biochemistry: NPXY motif of LDLR binds ARH and AP2 adaptor.

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Protein Sorting and Trafficking

Which mutation is associated with Familial Hypercholesterolemia (FH)?

Familial hypercholesterolemia prototypical autosomal co-dominant hyperlipidemia illustrating receptor-mediated endocytosis studied Brown Goldstein Nobel 1985 award. Clinical features elevated plasma LDL two to three fold heterozygotes six fold homozygotes tendon xanthomas cholesterol deposition xanthelasma corneal arcus premature atherosclerotic coronary disease often teens homozygotes severe. Molecular lesion mutations LDLR gene locus 19p13.2 encoding 860 aa receptor 18 exons. Over 2000 pathogenic variants classified five classes: class 1 null no synthesis, class 2 transport defective ER retention, class 3 binding defective LA repeat, class 4 internalization defective NPXY tail or ARH adaptor, class 5 recycling defective. Heterozygote prevalence 1 in 220, homozygote 1 in 300k to million. Pathway failure prevents hepatic uptake increasing circulating LDL cholesterol. Transferrin receptor mutations affect iron metabolism anemia, Hsp70 influences folding general, dynamin impairs vesicle scission not cholesterol specifically. Identification LDLR clarified endocytic regulation feedback via SREBP controlling HMG-CoA reductase and PCSK9 therapeutic target evolocumab relevant cardiology metabolism and genetics and personalized medicine.

Ref: Genetics Home Reference, Familial Hypercholesterolemia: LDLR mutations on 19p13.2 cause FH.

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Protein Sorting and Trafficking

What is the function of the LDL receptor in receptor-mediated endocytosis?

Maintenance systemic cholesterol homeostasis depends precise receptor-mediated recognition apolipoproteins decorating lipoproteins. Low-density lipoprotein particles contain single copy apolipoprotein B-100 enormous 4536 amino acid amphipathic protein wrapping hydrophobic cholesteryl ester core exposing receptor binding domain rich basic arginine lysine around 3000-4000 position. LDL receptor extracellular region comprises seven cysteine-rich ligand-binding repeats LA1-LA7 each coordinating calcium via acidic residues Complementarity to basic ligand. Additional EGF precursor homology domain beta-propeller responsible acid-dependent ligand release endosome pH 5.5 conformational change. After synthesis ER folded with Rap chaperone processed Golgi receptors reside plasma membrane clustering coated pits via cytosolic FXNPXY interaction indirectly via ARH Dab2 adaptors linking AP2 mu2 beta2. Binding LDL neutral pH triggers rapid internalization minutes; LDL degraded lysosomes cholesterol esters hydrolyzed acid lipase releasing free cholesterol suppressing SREBP pathway HMG-CoA reductase. Transferrin receptor binds iron-laden transferrin distinct site handles iron not lipoproteins. LDL receptor does not function ubiquitin ligase or proteasome regulator. Specificity apoB-100 defines receptor linking endocytosis whole-body cholesterol balance physiology.

Ref: Brown & Goldstein, Science 1986 and Nobel Lecture: LDL receptor binds apoB-100.

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