Low-density lipoprotein (LDL) receptor class A, conserved site <p>Low-density lipoprotein (LDL) receptors are the major cholesterol-carrying lipoproteins of plasma. Seven successive cysteine-rich repeats of about 40 amino acids are present in the N-terminal of this multidomain membrane protein [<cite idref="PUB00000798"/>]. Similar domains have been found (see references in [<cite idref="PUB00004868"/>]) in other extracellular and membrane proteins which are listed below: </p><ul><li>Vertebrate very low density lipoprotein (VLDL) receptor, which binds and transports VLDL. Its extracellular domain is composed of 8 LDLRA domains, 3 EGF-like domains and 6 LDL-receptor class B domains (LDLRB). </li><li> Vertebrate low-density lipoprotein receptor-related protein 1 (LRP1) (reviewed in [<cite idref="PUB00000086"/>]), which may act as a receptor for the endocytosis of extracellular ligands. LRP1 contains 31 LDLRA domains and 22 EGF-like domains. </li><li> Vertebrate low-density lipoprotein receptor-related protein 2 (LRP2) (also known as gp330 or megalin). LRP2 contains 36 LDLRA domains and 17 EGF-like domains. </li><li> A LRP-homologue from Caenorhabditis elegans, which contains 35 LDLRA domains and 17 EGF-like domains. </li><li> Drosophila putative vitellogenin receptor, with 13 copies of LDLRA domains and 17 EGF-like repeats. </li><li> Complement factor I, which is responsible for cleaving the alpha-chains of C4b and C3b. It consists of a FIMAC domain (Factor I/MAC proteins C6/C7), a scavenger receptor-like domain, 2 copies of LDLRA and a C-terminal serine protease domain. </li><li> Complement components C6, C7, C8 and C9. They contain each one LDLRA domain. </li><li> Perlecan, a large multidomain basement membrane heparan sulphate proteoglycan composed of 4 LDLRA domains, 3 LamB domains, 12 laminin EGF- like domains, 14-21 IG-like domains, 3 LamG domains, and 4 EGF-like domains. A similar but shorter proteoglycan (UNC52) is found in Caenorhabditis elegans which has 3 repeats of LDLRA. </li><li> Invertebrate giant extracellular hemoglobin linker chains, which allow heme-containing chains to construct giant hemoglobin (1 LDLRA domain). </li><li> G-protein coupled receptor Grl101 of the snail Lymnaea stagnalis, which might directly transduce signals carried by large extracellular proteins. </li><li> Vertebrate enterokinase (EC 3.4.21.9), a type II membrane protein of the intestinal brush border, which activates trypsinogen. It consists at least of a catalytic light chain and a multidomain heavy chain which has 2 LDLRA, a MAM domain (see <db_xref db="PROSITEDOC" dbkey="PDOC00604"/>), a SRCR domain (see <db_xref db="PROSITEDOC" dbkey="PDOC00348"/>) and a CUB domain (see <db_xref db="PROSITEDOC" dbkey="PDOC00908"/>).</li><li> Human autosomal dominant polycystic kidney disease protein 1 (PKD1), which is involved in adhesive protein-protein and protein-carbohydrate interactions. The potential calcium-binding site of its single LDLRA domain is missing. </li><li> Vertebrate integral membrane protein DGCR2/IDD, a potential adhesion receptor with 1 LDLRA domain, a C-type lectin and a VWFC domain (see <db_xref db="PROSITEDOC" dbkey="PDOC00928"/>).</li><li> Drosophila serine protease nudel (EC 3.4.21.-), which is involved in the induction of dorsoventral polarity of the embryo. It has 11 LDLRA domains, 3 of which miss the first disulphide bond (C1-C3). </li><li> Avian subgroup A rous sarcoma virus receptor (1 copy of LDLRA). </li><li> Bovine Sco-spondin, which is secreted by the subcommissural organ in embryos and is involved in the modulation of neuronal aggregation. It contains at least 2 EGF-like domains and 3 LDLRA domains. </li></ul><p>The LDL-receptor class A domain contains 6 disulphide-bound cysteines [<cite idref="PUB00000411"/>] and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module [<cite idref="PUB00004868"/>]. A schematic representation of this domain is shown here: </p><pre> +---------------------+ +--------------------------------+ | | | | -CxxxxxxxxxxxxCxxxxxxxxCxxxxxxxxCxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxC- | ******************************************* | | +----------------------------+'C': conserved cysteine involved in a disulphide bond.'x': any residue.'*': position of the pattern.</pre><p>In LDL-receptors the class A domains form the binding site for LDL [<cite idref="PUB00000798"/>] and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands [<cite idref="PUB00005112"/>]. The repeat has been shown [<cite idref="PUB00004868"/>] to consist of a beta-hairpin structure followed by a series of beta-turns. The binding of calcium seems to induce no significant conformational change.</p>