BMP6 binding to heparin and heparan sulfate is mediated by N-terminal and C-terminal clustered basic residues

The bone morphogenetic protein 6 (BMP6) is a crucial inducer of hepcidin, the peptide hormone that regulates iron availability in our body. Hepcidin expression influenced by hepatic heparan sulfate (HS) and heparin administration, suggesting BMP6 interaction with heparin/HS. BMP2/4 subfamily has been deeply characterized to have N-terminal heparin/HS binding domain (HBD), whose basic residues contact groups on HS. Such detailed characterization still required for other, structurally different BMPs, including BMP6. peptides encompassing potential HBDs were analysed heparin-functionalized plates microcantilevers, membrane HS expressing CHO-K1 cells. Monomeric wild-type mutants produced, substituting non-charged ones, their affinity heparin-column was measured. BMP6-heparin also predicted at atomic level silico molecular dynamics. C-terminal showed high solid-phase assays. mutation two sites (R5L, R6S, R7L K126N, K127N, R129S) abolished heparin-binding activity recombinant monomeric specifically bound cells through same domains. Molecular dynamic studies supported role HBDs, cooperative behaviour. In BMP6, (R5, R6, R7) (K126, K127, R129) domains mediate This study provides mechanism supporting use sequester inhibit hepcidin expression, novel clinical approach high-hepcidin disorders.