PROSITE documentation PDOC00929

LDL-receptor class A (LDLRA) domain signature and profile




Description

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.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

LDLRA_2, PS50068; LDL-receptor class A (LDLRA) domain profile  (MATRIX)

LDLRA_1, PS01209; LDL-receptor class A (LDLRA) domain signature  (PATTERN)


References

1AuthorsYamamoto T., Davis C.G., Brown M.S., Schneider W.J., Casey M.L., Goldstein J.L., Russell D.W.
TitleThe human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.
SourceCell 39:27-38(1984).
PubMed ID6091915

2AuthorsDaly N.L., Scanlon M.J., Djordjevic J.T., Kroon P.A., Smith R.
TitleThree-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.
SourceProc. Natl. Acad. Sci. U.S.A. 92:6334-6338(1995).
PubMed ID7603991

3AuthorsKrieger M., Herz J.
TitleStructures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).
SourceAnnu. Rev. Biochem. 63:601-637(1994).
PubMed ID7979249
DOI10.1146/annurev.bi.63.070194.003125

4AuthorsBieri S., Djordjevic J.T., Daly N.L., Smith R., Kroon P.A.
TitleDisulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.
SourceBiochemistry 34:13059-13065(1995).
PubMed ID7548065

5Authorsvan Driel I.R., Goldstein J.L., Suedhof T.C., Brown M.S.
SourceJ. Biol. Chem. 262:17443-17449(1987).

6AuthorsMahley R.W.
TitleApolipoprotein E: cholesterol transport protein with expanding role in cell biology.
SourceScience 240:622-630(1988).
PubMed ID3283935



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