Figure 7

Hypothesis for the role of HDGF in gene regulation. The HDGF molecule comprises an N-terminal PWWP domain and a C-terminus (red oval). Step 1, At a higher concentration, HDGF may interact with heparin on the cell surface with an enhanced binding affinity via its dimeric structure or bind to heparin with a monomeric form with a low affinity, or alternatively bind to the membrane receptor, NCL. Step 2, Dimeric or monomeric HDGF recognizes the receptor on the nuclear pole with its specific sequence of NLS2 in the variable C-terminus to translocate HDGF into the nucleus after internalization into the cell. Step 3, Either monomers or dimers of HDGF might exist inside the nucleus. The HDGF undergoes domain swapping to form a rigid dimer linked with a flexible hinge loop, which is transformed into a helix αC when approaching the histone or DNA fibres, as shown in the enlarged box. HDGF might lie across two DNA fibres because the structural dimension of a dimer is larger than the distance between two DNA fibres, or it might slide over one DNA fibre through its highly conserved PWWP domain. Step 4, After the PWWP domain is activated by methyl peptides in histone and recognizes the promoter, HDGF might alter its C-terminal conformation (red triangle) and participate in regulating the gene expression through its variable C-terminus.