Question

4. Briefly describe the “two step” mechanism of alpha secretase (TACE) activation.

5. What is the role of PMA in alpha secretase (TACE) activation?

Answer 1

Question 4

Tumor necrosis factor-alfa converting enzyme (TACE) is a member of the Type I membrane protein family of disintegrin and metalloproteinase (ADAM), which mediates the shedding of adhesion proteins and membrane-anchored signaling in the ectodomain. TACE shows alpha-secretase activity. TACE is produced as an inactive zymogen and is then converted to the catalytically active form in a proteolytic process. Active TACE was produced by proteolytic cleavage to zymogen by PC7 and furin. Removal of the prodomain (zymogen protein sequence) happens after the protein leaves the medial Golgi, just before it appears on the surface of the cells. TACE contains the putative sequence of recognition of proprotein-convertase (RVKR), which is assumed to be used to produce the mature enzyme. It is believed that PC7 and furin cleave zymogen in RVKR domain during maturation of protein in the Golgi. Protein transfer from one cisterna of Golgi complex to another by endocytosis.

Question 5

PMA has a negative effect on the activation of TACE. TACE is degraded in the presence of PMA. PMA prevents endocytosis and therefore inhibits TACE activation.