The role of the C-terminal domain of PCSK9 and SEC24 isoforms in PCSK9 secretion

Publication date: Available online 11 February 2020Source: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of LipidsAuthor(s): Shi-jun Deng, Yishi Shen, Hong-mei Gu, Shoudong Guo, Shan-Rong Wu, Da-wei ZhangAbstractProprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that promotes low-density lipoprotein receptor (LDLR) degradation and thereby regulating plasma levels of LDL cholesterol. Previous studies have revealed the role of the C-terminal domain (CTD) of PCSK9 in its secretion, however, how CTD regulates PCSK9 secretion is not completely understood. Additionally, SEC24A, the cargo adaptor protein of the coat protein complex II, has been implicated in the secretion of mouse PCSK9. Here, we investigated how CTD and SEC24 regulated PCSK9 secretion in humans. We found that mutant PCSK91–528, in which amino acids from 529 to the end (amino acid 692) were deleted, was maturated and secreted from cells as effectively as the wild-type protein. On the other hand, lacking amino acids 454 to 692 in mutant PCSK91–453 significantly reduced its maturation and secretion, but to a lesser extent when compared to mutants PCSK91–446, PCSK91–445 and PCSK91–444, that all markedly impaired PCSK9 maturation. However, mutant PCSK91–444 virtually eliminated PCSK9 secretion while PCSK91–446 and PCSK91–445 could still be adequately detected in culture medium. Interestingly, mutation of Pro445 to other amino acid residues considerably impaire...

Source: Biochimica et Biophysica Acta (BBA) Molecular and Cell Biology of Lipids - February 12, 2020 Category: Lipidology Source Type: research