Gene The<unk> R gene resides on chromosome 19 at the band 19p13.2 and is split into 18 exons. Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the epidermal growth factor (EGF) domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code the cytosolic domain. This gene produces 6 isoforms through alternative splicing. Protein This protein belongs to the<unk> R family and is made up of a number of functionally distinct domains, including 3 EGF-like domains, 7<unk> -R class A domains, and 6<unk> -R class B repeats. The N-terminal domain of the<unk> , which is responsible for ligand binding, is composed of seven sequence repeats (~50% identical). Each repeat, referred to as a class A repeat or<unk> -A, contains roughly 40 amino acids, including 6 cysteine residues that form disulfide bonds within the repeat. Additionally, each repeat has highly conserved acidic residues which it uses to coordinate a single calcium ion in an octahedral lattice. Both the disulfide bonds and calcium coordination are necessary for the structural integrity of the domain during the receptor's repeated trips to the highly acidic interior of the endosome. The exact mechanism of interaction between the class A repeats and ligand <unk>  is unknown, but it is thought that the repeats act as "grabbers" to hold the<unk> . Binding of ApoB requires repeats 2-7 while binding ApoE requires only repeat 5 (thought to be the ancestral repeat). Next to the ligand binding domain is an EGF precursor homology domain (EGFP domain). This shows approximately 30% homology with the EGF precursor gene. There are three "growth factor" repeats; A, B and C. A and B are closely linked while C is separated by the YWTD repeat region, which adopts a beta-propeller conformation <unk> -R class B domain). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound<unk>  to be released in the endosome. A third domain of the protein is rich in O-linked oligosaccharides but appears to show little function. Knockout experiments have confirmed that no significant loss of activity occurs without this domain. It has been speculated that the domain may have ancestrally acted as a spacer to push the receptor beyond the extracellular matrix. The single transmembrane domain of 22 (mostly) non-polar residues crosses the plasma membrane in a single alpha helix. The cytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors to clathrin-coated pits and for triggering receptor-mediated endocytosis after binding. Portions of the cytosolic sequence have been found in other lipoprotein receptors, as well as in more distant receptor relatives. Mutations Mutations in the gene encoding the<unk>  are known to cause familial hypercholesterolaemia. There are 5 broad classes of mutation of the<unk> : * Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER). * Class 2 mutations prevent proper transport to the Golgi body needed for modifications to the receptor. *e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein. * Class 3 mutations stop the binding of<unk>  to the receptor. *e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted. * Class 4 mutations inhibit the internalization of the receptor-ligand complex. *e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; C residue converted to a Y, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of<unk> , therefore this mutation inhibits<unk>  internalization. * Class 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface (but all must be newly synthesised).
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