Structural basis for the high‐affinity interaction of nidogen‐1 with immunoglobulin‐like domain 3 of perlecan

Nidogen and perlecan are large multifunctional basement membrane (BM) proteins conserved in all metazoa. Their high‐affinity interaction, which is likely to contribute to BM assembly and function, is mediated by the central G2 domain in nidogen and the third immunoglobulin (IG)‐like domain in perlecan, IG3. We have solved the crystal structure at 2.0 Å resolution of the mouse nidogen‐1 G2–perlecan IG3 complex. Perlecan IG3 belongs to the I‐set of the IG superfamily and binds to the wall of the nidogen‐1 G2 β‐barrel using β‐strands C, D and F. Nidogen‐1 residues participating in the extensive interface are highly conserved, whereas the corresponding binding site on perlecan is more variable. We hypothesize that a second, as yet unidentified, activity of nidogen overlaps with perlecan binding and accounts for the unusually high degree of surface conservation in the G2 domain.