Figure 1

Multidomain structure of RELN. (a) Full structure of RELN in a schematic, multidomain representation and its proteolytic fragments after N- and C-terminal processing by ADAMTS-4 (P1244-A2688) are displayed. Green rectangles represent BNR domains, and EGF domains are colored in dark pink. RELN contains eight subunits, which consist of BNR-EGF-BNR domains (BEB). The blue box denotes the central part of RELN that was studied in the paper. Red dots show Zn²⁺ binding sites and yellow crosses represent cysteines that do not form a disulfide bond. C2101 located in BEB5 is responsible for RELN homodimerization. The enzymatically decisive serine residue in the GKS₁₂₈₃D sequence is indicated by a blue rectangle. The crystal structure in the inset shows the 3-D structure shared by BEB modules with all possible disulfide bonds displayed: (i) disulfide bonds within an EGF domain (named SS), (ii) disulfide bonds that zip BNR domains (SS₁ in subunit BNR-A and SS₂ in subunit BNR-B), (iii) a disulfide bond that keeps together a loop comprised of residues 8–12 (SS₃), and (iv) a disulfide bond that links BNR11 with BNR12 (SS₀) which is characteristic to BEB6 only. Close views of Zn²⁺ binding sites in (b) BEB6 and (c) BEB5 are displayed in the insets. Residues which coordinate Zn²⁺ are shown: H2061, H2074, E2264 (in BEB5) and E2397, E2399, H2460 (in BEB6). The yellow fragment of the protein (whose sequence is displayed) corresponds to the loop located in vicinity of the Zn²⁺ binding site and protected by SS₃ in both BEB5 and BEB6 modules. The SS₀ bond (orange) is also displayed in BEB6.