The Folded Protein Modules of the C-terminal G3 Domain of Aggrecan Can Each Facilitate the Translocation and Secretion of the Extended Chondroitin Sulfate Attachment Sequence*

Aggrecan is a multidomain proteoglycan containing both extended and folded protein modules. The C-terminal G3 domain contains a lectin-like, complement regulatory protein-like, and two alternatively spliced epidermal growth factor-like modules. It has been proposed that the lectin module alone has a necessary role in the intracellular translocation and secretion of proteins expressed containing G3. Constructs containing human aggrecan G3 together with 1155 bases of the adjacent chondroitin sulfate attachment region (CS-2) were prepared with different combinations and deletions of the protein modules and transfected into mammalian cells of monkey or hamster origin. The results showed that the products containing only the unfolded protein sequences (CS-2 with or without the C-terminal tail sequence) were translated and accumulated intracellularly but were not secreted. In contrast the constructs containing any of the folded protein modules and the extended CS-2 region were translated and secreted from the cells. The results show that the lectin module was not unique in facilitating the intracellular translocation and secretion of the G3 domain. The conservation of G3-like domains within the aggrecan family of proteoglycans may therefore result from their participation in other extracellular functions.