Low density lipoprotein (LDL) is the major cholesterol-carrying lipoprotein of plasma. The receptor protein binds LDL and transports it into cells by endocytosis. In order to be internalised, the receptor-ligand complex must first cluster into clathrin-coated pits. Seven successive cysteine-rich repeats of about 40 amino acids are present in the N-terminal of this multidomain membrane protein [ 6091915].
The LDL-receptor class A domain contains 6 disulphide-bound cysteines [7548065] and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module [7603991]. A schematic representation of this domain is shown here:
+---------------------+ +--------------------------------+
| | | |
-CxxxxxxxxxxxxCxxxxxxxxCxxxxxxxxCxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxC-
| |
+----------------------------+
'C': conserved cysteine involved in a disulphide bond.
'x': any residue.
In LDL-receptors the class A domains form the binding site for LDL [6091915] and calcium [3320043]. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands [3283935]. The repeat has been shown [7603991] to consist of a beta-hairpin structure followed by a series of beta turns. In the absence of calcium, LDL-A domains are unstructured; the bound calcium ion imparts structural integrity.
Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor [6327078, 6091915]. Similar domains have been found (see references in [7603991]) in several extracellular and membrane proteins (see examples).
Numerous familial hypercholestorolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.
| 
0
