PROSITE documentation PDOC00929
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{PDOC00929}
{PS01209; LDLRA_1}
{PS50068; LDLRA_2}
{BEGIN}
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* LDL-receptor class A (LDLRA) domain signature and profile *
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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 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.
- 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 beta-hairpin
structure followed by a series of beta turns. The binding of calcium seems to
induce no significant conformational change.
-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.
-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: 1.
-Last update: April 2006 / Pattern revised.
[ 1] Yamamoto T., Davis C.G., Brown M.S., Schneider W.J., Casey M.L.,
Goldstein J.L., Russell D.W.
"The human LDL receptor: a cysteine-rich protein with multiple Alu
sequences in its mRNA."
Cell 39:27-38(1984).
PubMed=6091915
[ 2] Daly N.L., Scanlon M.J., Djordjevic J.T., Kroon P.A., Smith R.
"Three-dimensional structure of a cysteine-rich repeat from the
low-density lipoprotein receptor."
Proc. Natl. Acad. Sci. U.S.A. 92:6334-6338(1995).
PubMed=7603991
[ 3] Krieger M., Herz J.
"Structures and functions of multiligand lipoprotein receptors:
macrophage scavenger receptors and LDL receptor-related protein
(LRP)."
Annu. Rev. Biochem. 63:601-637(1994).
PubMed=7979249; DOI=10.1146/annurev.bi.63.070194.003125
[ 4] Bieri S., Djordjevic J.T., Daly N.L., Smith R., Kroon P.A.
"Disulfide bridges of a cysteine-rich repeat of the LDL receptor
ligand-binding domain."
Biochemistry 34:13059-13065(1995).
PubMed=7548065
[ 5] van Driel I.R., Goldstein J.L., Suedhof T.C., Brown M.S.
J. Biol. Chem. 262:17443-17449(1987).
[ 6] Mahley R.W.
"Apolipoprotein E: cholesterol transport protein with expanding role
in cell biology."
Science 240:622-630(1988).
PubMed=3283935
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