Low density lipoprotein receptor gene family

The low density lipoprotein receptor gene family code for a class of structurally closely related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis (maintenance of appropriate concentration of cholesterol). In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed in the liver by the endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.

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There are seven members of the LDLR family in mammals, namely:

• LDLR
• VLDL receptor (VLDLR)
• ApoER2, or LRP8
• Multiple epidermal growth factor (EGF) repeat-containing protein (MEGF7)
• LDLR-related protein 1 (LRP1)
• LDLR-related protein 1b (LRP1b)
• Megalin.

See also: Soluble low density lipoprotein receptor-related protein (sLRP), whose impaired function is related to Alzheimer's Disease.

Structure

The members of the LDLR family are characterized by distinct functional domains present in characteristic numbers. These modules are:

• the type A binding repeats of 40 residues each, displaying a triple-disulfide-bond-stabilized negatively charged surface; certain head-to-tail combinations of these repeats are believed to specify ligand interactions;
• type B repeats, also containing six cysteines each;
• EGF repeats with YWTD beta propeller domain;
• a transmembrane domain, and
• the cytoplasmic region with (a) signal(s) for receptor internalization via coated pits, containing the consensus tetrapeptide Asn-Pro-Xaa-Tyr (NPxY). This cytoplasmic tail controls both endocytosis and signaling by interacting with the phosphotyrosine binding (PTB) domain-containing proteins.

References

• Nykjaer A, Willnow (2002) The low-density lipoprotein receptor gene family: a cellular Swiss army knife? Trends Cell Biol. 12(6):273-80. PMID 12074887

• Li Y, Lu W, Marzolo MP, Bu G (2001) Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates. J Biol Chem. 276(21):18000-6. PMID 11279214

• Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J. (2000) Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem. 275(33):25616-24. PMID 10827173

• Beffert U, Stolt PC, Herz J. (2004) Functions of lipoprotein receptors in neurons. J Lipid Res. 45(3):403-9. PMID 14657206