| Autor: |
Aiwu Zhang, Ronald E. Painter, Stephen F. Previs, Shuo Quan, Heather Zhou, Adam B. Weinglass, Anka G. Ehrhardt, Daphne Szeto, Michael Kavana, Sheng-Ping Wang, Dan Xie, Marina Ichetovkin, Brian K. Hubbard, Larissa Wilsie, Karen O. Akinsanya, Thomas P. Roddy, Oksana C Palyha, Jing Xiao, Mark Rosenbach, Alison M. Strack, Donald Chu, Weihua Ni, Douglas Wisniewski, Douglas G. Johns, Jim Milligan, Paul A. Fischer, Sookhee Ha, Xi Ai, George H. Addona, Thomas F. Vogt, Gail Forrest, Jennifer Baysarowich |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Biochemistry & Molecular Biology Journal. |
| ISSN: |
2471-8084 |
| DOI: |
10.21767/2471-8084.100026 |
| Popis: |
Human genetics and pharmacologic clinical intervention demonstrate the key role of PCSK9 in cholesterol regulation. To understand the role of the C-terminal domain of PCSK9, two human mutations in this region (S462P and A522T PCSK9) have been profiled. Confirming and extending previous observations, S462P and WT PCSK9 bind to LDLR with equivalent affinity; however, while S462P PCSK9 cleavage is unaffected, its secretion is defective, and association with the ER protein-folding sensor calreticulin, increased. In a similar manner, A522T PCSK9 also exhibits defective secretion and an enhanced association with calreticulin. To assess the in vivo lipid phenotype of the S462P and A522T PCSK9 mutations, Pcsk9-/- mice were infected with AAV8’s encoding the different variants. Although liver transcript levels for all were equivalent, circulating levels of S462P PCSK9, and to a lesser degree A522T PCSK9, were reduced relative to WT PCSK9 correlating with the in vitro phenotype. Further, the extent of reduced circulating S462P or A522T PCSK9 correlated well with increases in mouse liver LDLR and reductions of LDL/ total cholesterol. When interpreted within the context of molecular modeling, it appears that the human non-synonymous polymorphisms S462P and A522T destabilize the C-terminal domain of PCSK9 impacting folding and secretion. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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