Figure 1

(A) Schematic representation of the domain architecture of the LRP, with domains suggested to contain a Ca²⁺ binding site as shown in gray. For estimation of the stoichiometric binding of Ca²⁺ to the entire LRP molecule, each CR-domain is a potential cation carrier based on the fact that all CR-domain structures described so far include a bound Ca²⁺ ion [5–7]. The crystal structure of the LDLR YWTD-repeated β-propeller does not show any cations and we assume similar lack of Ca²⁺ binding to these fragments within LRP. In contrast, some EGF-domains do bind Ca²⁺ and some do not. For LDLR the EGF-domain pair amino-terminal to the β-propeller binds 2 Ca²⁺ ions, and accordingly, it is assumed that the four EGF-domain pairs within LRP are also Ca²⁺ binding. The carboxy-terminal EGF-domain is not chelating a Ca²⁺ ion [7–11]. By these assumptions, one LRP molecules could bind a total of at least 39 Ca²⁺ ions. Rectangles () represent CR-domains, pentagons () represent EGF-domains, and hexagonals () for each blade of the β-propellers. (B) Ribbon representation of the canonical CR-domain folding and Ca²⁺ binding site. Left, the backbone folding of CR5^LDLR (Protein Data Bank accession code 1ajj [5]) showing the location of the Ca²⁺ ion indicated as the sphere. Right, zoom of the Ca²⁺ cage showing the octahedral cation coordination. (C) Alignment of the primary structures of Ca²⁺-binding CR-domains with a known 3D-structure, the first, the second, the fifth, and the sixth CR-domain from LDLR, and the third, the seventh, and the eighth CR-domain from LRP. The symbols below the alignment indicate residues involved in Ca²⁺ chelation (‡, coordination by backbone carbonyl; †, coordination by side chain carboxyl), and the six conserved cysteines are indicated above the sequences with roman numbers.