PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide

被引：164

作者：

Shan, LiXin ^{[1
]}

Pang, Ling ^{[1
]}

Zhang, Rumin ^{[2
]}

Murgolo, Nicholas J. ^{[2
]}

Lan, Hong ^{[1
]}

Hedrick, Joseph A. ^{[1
]}

机构：

[1] Schering Plough Res Inst, Dept Cardiovasc & Metab Dis Res, Kenilworth, NJ 07033 USA

[2] Schering Plough Res Inst, Dept Discovery Technol, Kenilworth, NJ 07033 USA

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2008年 / 375卷 / 01期

关键词：

PCSK9; low density lipoprotein receptor; LDLR; LDL; LDL receptor associated protein; EGF-A domain;

D O I：

10.1016/j.bbrc.2008.07.106

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) and induces its internalization and degradation. PCSK9 binding to LDLR is mediated through the LDLR epidermal growth factor-like repeat A (EGF-A) domain. We show for the first time that an EGF-A peptide inhibits PCSK9-mediated degradation of LDLR in HepG2 cells. In addition to LDLR, we show that PCSK9 also binds directly to ApoER2 and mouse VLDLR. Importantly, binding of PCSK9 to either LDLR or mouse VLDLR was effectively inhibited by EGF-A while binding to ApoER2 was less affected. In contrast, LDL receptor-associated protein (RAP), which interacts with LDL receptor repeat type A (LA) domains, inhibited PCSK9 binding to ApoER2 with greater efficacy than either LDLR or mVLDLR. These data demonstrate that while PCSK9 binds several receptors via its EGF-A binding domain, additional contacts with other receptor domains are also involved. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：69 / 73

页数：5

共 28 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] 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

[3] Proapoptotic effects of NARC 1 (=PCSK9), the gene encoding a novel serine proteinase [J].

Bingham, Brendan ;

Shen, Ru ;

Kotnis, Smita ;

Lo, C. Frederick ;

Ozenberger, Bradley A. ;

Ghosh, Nivedita. ;

Kennedy, Jeffrey D. ;

Jacobsen, J. Steven ;

Grenier, Jill M. ;

DiStefano, Peter S. ;

Chiang, Lillian W. ;

Wood, Andrew .

CYTOMETRY PART A, 2006, 69A (11) :1123-1131

[4] Biomedicine - Lowering LDL - Not only how low, but how long? [J].

Brown, MS ;

Goldstein, JL .

SCIENCE, 2006, 311 (5768) :1721-1723

[5] Low LDL cholesterol in African Americans resulting from frequent nonsense mutations in PCSK9 [J].

Cohen, J ;

Pertsemlidis, A ;

Kotowski, IK ;

Graham, R ;

Garcia, CK ;

Hobbs, HH .

NATURE GENETICS, 2005, 37 (03) :328-328

[6] Sequence variations in PCSK9, low LDL, and protection against coronary heart disease [J].

Cohen, JC ;

Boerwinkle, E ;

Mosley, TH ;

Hobbs, HH .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (12) :1264-1272

[7] Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia [J].

Cunningham, David ;

Danley, Dennis E. ;

Geoghegan, Kieran F. ;

Griffor, Matthew C. ;

Hawkins, Julie L. ;

Subashi, Timothy A. ;

Varghese, Alison H. ;

Ammirati, Mark J. ;

Culp, Jeffrey S. ;

Hoth, Lise R. ;

Mansour, Mahmoud N. ;

McGrath, Katherine M. ;

Seddon, Andrew P. ;

Shenolikar, Shirish ;

Stutzman-Engwall, Kim J. ;

Warren, Laurie C. ;

Xia, Donghui ;

Qiu, Xiayang .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2007, 14 (05) :413-419

[8] Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors [J].

Fisher, C ;

Beglova, N ;

Blacklow, SC .

MOLECULAR CELL, 2006, 22 (02) :277-283

[9] Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation [J].

Fisher, Timothy S. ;

Lo Surdo, Paola ;

Pandit, Shilpa ;

Mattu, Marco ;

Santoro, Joseph C. ;

Wisniewski, Doug ;

Cummings, Richard T. ;

Calzetta, Alessandra ;

Cubbon, Rose M. ;

Fischer, Paul A. ;

Tarachandani, Anil ;

De Francesco, Raffaele ;

Wright, Samuel D. ;

Sparrow, Carl P. ;

Carfi, Andrea ;

Sitlani, Ayesha .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (28) :20502-20512

[10] What promise does PCSK9 hold? [J].

Kastelein, JJP ;

Fouchier, SW ;

Defesche, JC .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2005, 45 (10) :1620-1621

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