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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.

April 2006 / Pattern revised.

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

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

Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: 1.

• Domain architecture view of Swiss-Prot proteins matching PS50068 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS50068 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS50068 • Scan Swiss-Prot/TrEMBL entries against PS50068 • view ligand binding statistics

Matching PDB structures: 1AJJ 1CR8 1D2J 1D2L ... [ALL]

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

Consensus pattern: C-[VILMA]-x(5,6)-C-[DNH]-x(3)-[DENQHT]-C-x(3,4)-[STADEW]-[DEH]-[DE]-x(1,5)-C The 4 C's are involved in disulfide bonds Sequences known to belong to this class detected by the pattern: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS01209 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS01209 • Scan Swiss-Prot/TrEMBL entries against PS01209 • view ligand binding statistics

Matching PDB structures: 1AJJ 1CR8 1D2J 1D2L ... [ALL]

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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