Molecular basis of PCSK9 function

被引：165

作者：

Lambert, Gilles ^{[1
,2
]}

Charlton, Francesca ^{[1
]}

Rye, Kerry-Anne ^{[1
]}

Piper, Derek E. ^{[3
]}

机构：

[1] Heart Res Inst, 114 Pyrmont Bridge Rd, Camperdown, NSW 2050, Australia

[2] Univ Nantes, UFR Med, F-44000 Nantes, France

[3] Amgen Inc, San Francisco, CA 94080 USA

来源：

ATHEROSCLEROSIS | 2009年 / 203卷 / 01期

关键词：

Hypercholesterolemia; LDL receptor; PCSK9; Therapeutic target; DENSITY-LIPOPROTEIN RECEPTOR; AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; CONVERTASE SUBTILISIN/KEXIN TYPE-9; PLASMA LDL-CHOLESTEROL; FAMILIAL HYPERCHOLESTEROLEMIA; SECRETED PCSK9; PROPROTEIN CONVERTASES; HEPG2; CELLS; SERUM LDL; RAT-LIVER;

D O I：

10.1016/j.atherosclerosis.2008.06.010

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The LDL receptor (LDLr) inhibitor Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) has emerged as a genetically validated target for lowering plasma LDL cholesterol levels. In 2007, PCSK9 was found to act as a chaperone that binds the LDLr, thereby targeting it for lysosomal degradation. The enzymatic activity of PCSK9 is not involved in that process, but rather permits proper intramolecular processing of PCSK9. This was demonstrated by both site directed mutagenesis and independent reports of the PCSK9 crystal structure. These reports also elucidated the mode of action of several naturally occurring mutants of PCSK9 associated with hyper- or hypocholesterolemia. The present review summarizes studies published or in print before May 2008 investigating the functional significance of PCSK9 and its promising aspects as a prognostic tool and a drug target. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

引用

页码：1 / 7

页数：7

共 73 条

[1] Mutations in PCSK9 cause autosomal dominant hypercholesterolemia [J].

Abifadel, M ;

Varret, M ;

Rabès, JP ;

Allard, D ;

Ouguerram, K ;

Devillers, M ;

Cruaud, C ;

Benjannet, S ;

Wickham, L ;

Erlich, D ;

Derré, A ;

Villéger, L ;

Farnier, M ;

Beucler, I ;

Bruckert, E ;

Chambaz, J ;

Chanu, B ;

Lecerf, JM ;

Luc, G ;

Moulin, P ;

Weissenbach, J ;

Prat, A ;

Krempf, M ;

Junien, C ;

Seidah, NG ;

Boileau, C .

NATURE GENETICS, 2003, 34 (02) :154-156

[2] Serum proprotein convertase subtilisin Kexin type 9 is correlated directly with serum LDL cholesterol [J].

Alborn, William E. ;

Cao, Guoqing ;

Careskey, Holly E. ;

Qian, Yue-Wei ;

Subramaniam, Danise R. ;

Davies, Julian ;

Conner, Elaine M. ;

Konrad, Robert J. .

CLINICAL CHEMISTRY, 2007, 53 (10) :1814-1819

[3]

Allard Delphine, 2005, Hum Mutat, V26, P497, DOI 10.1002/humu.9383

[4] Inhibition of squalene synthase upregulates PCSK9 expression in rat liver [J].

Bedi, Mohini ;

Niesen, Melissa ;

Lopez, Dayami .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2008, 470 (02) :116-119

[5] The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A-Functional consequences of natural mutations and post-translational modifications [J].

Benjannet, Suzanne ;

Rhainds, David ;

Hamelin, Josee ;

Nassoury, Nasha ;

Seidah, Nabil G. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (41) :30561-30572

[6] Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy [J].

Berge, KE ;

Ose, L ;

Leren, TP .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2006, 26 (05) :1094-1100

[7] Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers [J].

Blacklow, Stephen C. .

CURRENT OPINION IN STRUCTURAL BIOLOGY, 2007, 17 (04) :419-426

[8] Familial hypercholesterolaemia in Portugal [J].

Bourbon, M. ;

Alves, A. C. ;

Medeiros, A. M. ;

Silva, S. ;

Soutar, A. K. .

ATHEROSCLEROSIS, 2008, 196 (02) :633-642

[9] Characterization of novel mutations in the catalytic domain of the PCSK9 gene [J].

Cameron, J. ;

Holla, O. L. ;

Laerdahl, J. K. ;

Kulseth, M. A. ;

Ranheim, T. ;

Rognes, T. ;

Berge, K. E. ;

Leren, T. P. .

JOURNAL OF INTERNAL MEDICINE, 2008, 263 (04) :420-431

[10] Effect of mutations in the PCSK9 gene on the cell surface LDL receptors [J].

Cameron, J ;

Holla, OL ;

Ranheim, T ;

Kulseth, MA ;

Berge, KE ;

Leren, TP .

HUMAN MOLECULAR GENETICS, 2006, 15 (09) :1551-1558

← 1 2 3 4 5 6 7 8 →