PROSITE documentation PDOC51120LDL-receptor class B (LDLRB) repeat profile
The low-density lipoprotein receptor (LDLR) regulates cholesterol homeostasis in mammalian cells. LDLR binds cholesterol-carrying LDL, associates with clathrin-coated pits, and is internalized into acidic endosomes where it separates from its ligand. The ligand is degraded in lysosomes, while the receptor returns to the cell surface [1]. The LDLR has several domains. The ligand-binding domain contains seven LDL receptor class A repeats (see <PDOC00929>), each with three disulfide bonds and a coordinated Ca2+ ion. The second conserved region contains two EGF repeats (see <PDOC00913>), followed by six YWTD or LDL receptor class B repeats and another EGF repeat [2]. This conserved region is critical for ligand release and recycling of the receptor [3].
The structure of the six YWTD repeats of LDL receptor have been solved (see <PDB:1IJQ>) [4]. The six YWTD repeats together fold into a six-bladed β-propeller. Each blade of the propeller consists of four antiparallel β-strands; the innermost strand of each blade is labeled 1 and the outermost strand, 4. The sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue YWTD repeat spans strands 2-4 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 2-4 from the first sequence repeat.
Some proteins known to contain LDL receptor class B repeats:
- Animal low-density lipoprotein receptor.
- Mammalian pro-epidermal growth factor precursor (EGF).
- Mammalian nidogen-2 precursor, a cell adhesion glycoprotein which is widely distributed in basement membranes.
- Vertebrate sortilin-related receptor precursor.
- Very low-density lipoprotein receptor precursor (VLDLR). It binds VLDL and transports it into cells by endocytosis.
- Drosophila Yolkless protein. It is involved in uptake of vitellogenin by endocytosis.
The profile we developed covers the whole LDL receptor class B repeat.
Last update:May 2005 / First entry.
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PROSITE method (with tools and information) covered by this documentation:
| 1 | Authors | Brown M.S. Goldstein J.L. |
| Title | A receptor-mediated pathway for cholesterol homeostasis. | |
| Source | Science 232:34-47(1986). | |
| PubMed ID | 3513311 |
| 2 | Authors | Springer T.A. |
| Title | An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. | |
| Source | J. Mol. Biol. 283:837-862(1998). | |
| PubMed ID | 9790844 |
| 3 | Authors | Davis C.G. Goldstein J.L. Sudhof T.C. Anderson R.G. Russell D.W. Brown M.S. |
| Title | Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. | |
| Source | Nature 326:760-765(1987). | |
| PubMed ID | 3494949 | |
| DOI | 10.1038/326760a0 |
| 4 | Authors | Jeon H. Meng W. Takagi J. Eck M.J. Springer T.A. Blacklow S.C. |
| Title | Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. | |
| Source | Nat. Struct. Biol. 8:499-504(2001). | |
| PubMed ID | 11373616 | |
| DOI | 10.1038/88556 |
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