Interplay of heparan sulfate chains with the core proteins of syndecans 2 and 4

Abstract

We have previously shown that the extracellular domains of the four syndecans are intrinsically disordered, and adopt a wide range of conformations. We report here the building of coarse‐grained models of the extracellular domains of human syndecans 2 and 4 using small‐angle X‐ray scattering restraints. One, two or three heparan sulfate (HS) hexadecasaccharides, (IdoA[2S]GlcNS[6S])8, were attached to three serine residues of the core proteins, resulting in eight variants for each syndecan that were used for all‐atom molecular dynamics (MD) simulations (0.5–1 µs). Syndecan‐4 had a larger conformational diversity than syndecan‐2, and remained extended during MD simulations in absence of HS whereas syndecan‐2 adopted more compact conformations. Their core proteins thus appeared to be structurally distinct. The HS chains also behave differently, the middle chain being more flexible in syndecan‐4, and the third chain being able to interact with the core protein regions mediating cell adhesion. The cell adhesion sites on both core proteins were flexible, with or without HS chains, the NXIP motif of syndecan‐2 being located in a particularly flexible region. In conclusion, the HS chains induce moderate changes in the conformational dynamics of both syndecans, depending on the number of HS chains and their location on the core protein, and on the core protein itself.