PROSITE documentation PDOC00929LDL-receptor class A (LDLRA) domain signature and profile
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 [1]. Similar domains have been found (see references in [2]) in other extracellular and membrane proteins which are listed below:
- 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).
- Vertebrate low-density lipoprotein receptor-related protein 1 (LRP1) (reviewed in [3]), which may act as a receptor for the endocytosis of extracellular ligands. LRP1 contains 31 LDLRA domains and 22 EGF-like domains.
- 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.
- A LRP-homolog from Caenorhabditis elegans, which contains 35 LDLRA domains and 17 EGF-like domains.
- Drosophila putative vitellogenin receptor, with 13 copies of LDLRA domains and 17 EGF-like repeats.
- Complement factor I, which is responsible for cleaving the α-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.
- Complement components C6, C7, C8 and C9. They contain each one LDLRA domain.
- Perlecan, a large multidomain basement membrane heparan sulfate 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.
- Invertebrate giant extracellular hemoglobin linker chains, which allow heme-containing chains to construct giant hemoglobin (1 LDLRA domain).
- G-protein coupled receptor Grl101 of the snail Lymnaea stagnalis, which might directly transduce signals carried by large extracellular proteins.
- 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 <PDOC00604>), a SRCR domain (see <PDOC00348>) and a CUB domain (see <PDOC00908>).
- 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.
- Vertebrate integral membrane protein DGCR2/IDD, a potential adhesion receptor with 1 LDLRA domain, a C-type lectin and a VWFC domain (see <PDOC00928>).
- 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 disulfide bond (C1-C3).
- Avian subgroup A rous sarcoma virus receptor (1 copy of LDLRA).
- 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.
The LDL-receptor class A domain contains 6 disulfide-bound cysteines [4] and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module [2]. A schematic representation of this domain is shown here:
+---------------------+ +--------------------------------+ | | | | -CxxxxxxxxxxxxCxxxxxxxxCxxxxxxxxCxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxC- | ******************************************* | | +----------------------------+
'C': conserved cysteine involved in a disulfide bond. 'x': any residue. '*': position of the pattern.
In LDL-receptors the class A domains form the binding site for LDL [1] and calcium [5]. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands [6]. The repeat has been shown [2] to consist of a β-hairpin structure followed by a series of β turns. The binding of calcium seems to induce no significant conformational change.
Last update:April 2006 / Pattern revised.
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PROSITE methods (with tools and information) covered by this documentation:
1 | Authors | Yamamoto T. Davis C.G. Brown M.S. Schneider W.J. Casey M.L. Goldstein J.L. Russell D.W. |
Title | The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. | |
Source | Cell 39:27-38(1984). | |
PubMed ID | 6091915 |
2 | Authors | Daly N.L. Scanlon M.J. Djordjevic J.T. Kroon P.A. Smith R. |
Title | Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. | |
Source | Proc. Natl. Acad. Sci. U.S.A. 92:6334-6338(1995). | |
PubMed ID | 7603991 |
3 | Authors | Krieger M. Herz J. |
Title | Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). | |
Source | Annu. Rev. Biochem. 63:601-637(1994). | |
PubMed ID | 7979249 | |
DOI | 10.1146/annurev.bi.63.070194.003125 |
4 | Authors | Bieri S. Djordjevic J.T. Daly N.L. Smith R. Kroon P.A. |
Title | Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain. | |
Source | Biochemistry 34:13059-13065(1995). | |
PubMed ID | 7548065 |
5 | Authors | van Driel I.R. Goldstein J.L. Suedhof T.C. Brown M.S. |
Source | J. Biol. Chem. 262:17443-17449(1987). |
6 | Authors | Mahley R.W. |
Title | Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. | |
Source | Science 240:622-630(1988). | |
PubMed ID | 3283935 |
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