Abstract
The plasma membrane is a barrier for endocytosis of macromolecules. There are many receptors and heparan sulfate proteoglycans (HSPG) at cell surface. HSPG plays a very important role in tuning the mammalian physiology including digestive, endocrine, nervous, and other systems. This study investigated the biological role of HSPG at internalization of cargos, using HATH domain of hepatoma-derived growth factor (HDGF) and cardiotoxins (CTX) A2 / A4 as two examples. The treatment of heparinase interfered the internalization at high dose of HATH domain and competition against low dose HATH domain inhibited the receptor mediated endocytosis pathway. In this study we demonstrate the enhancement of internalization of HATH domain was caused by HSPG. The early and late stages of internalization of HATH domain were through receptor and HSPG mediated endocytosis, respectively. One residue difference resulted in considerable difference in the amount of internalization between CTX A2 and A4. CTX A2 and A4 were specific to low or high sulfate HSPG and does not internalize through clathrin or caveolae mediated endocytosis. These two pathways were concern with receptor mediated endocytosis. HSPG mediated endocytosis was not via receptor mediated pathway and CTX A4 was via glypican enriched HSPG pathway. Although the CTX A2 and A4 maybe internalize through HSPG mediated endocytosis but they may interact with the different domain HSPG.