Key points are not available for this paper at this time.
The proprotein convertase subtilisin/kexin-type 9 (PCSK9), which promotes degradation of the hepatic low density lipoprotein receptor (LDLR), is now recognized as a major player in plasma cholesterol metabolism. Several gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, and thus, inhibition of PCSK9-induced degradation of the LDLR may be used to treat this deadly disease. Herein, we discovered an endogenous PCSK9 binding partner by Far Western blotting, co-immunoprecipitation, and pull-down assays. Following two-dimensional gel electrophoresis and mass spectrometry analysis, we demonstrated that PCSK9 binds to a ∼33-kDa protein identified as annexin A2 (AnxA2) but not to the closely related annexin A1. Furthermore, our functional LDLR assays and small hairpin RNA studies show that AnxA2 and the AnxA2·p11 complex could prevent PCSK9-directed LDLR degradation in HuH7, HepG2, and Chinese hamster ovary cells. Immunocytochemistry revealed that PCSK9 and AnxA2 co-localize at the cell surface, indicating a possible competition with the LDLR. Structure-function analyses demonstrated that the C-terminal cysteine-histidine-rich domain of PCSK9 interacts specifically with the N-terminal repeat R1 of AnxA2. Mutational analysis of this 70-amino acid-long repeat indicated that the RRTKK81 sequence of AnxA2 is implicated in this binding because its mutation to AATAA81 prevents its interaction with PCSK9. To our knowledge, this work constitutes the first to show that PCSK9 activity on LDLR can be regulated by an endogenous inhibitor. The identification of the minimal inhibitory sequence of AnxA2 should pave the way toward the development of PCSK9 inhibitory lead molecules for the treatment of hypercholesterolemia. The proprotein convertase subtilisin/kexin-type 9 (PCSK9), which promotes degradation of the hepatic low density lipoprotein receptor (LDLR), is now recognized as a major player in plasma cholesterol metabolism. Several gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, and thus, inhibition of PCSK9-induced degradation of the LDLR may be used to treat this deadly disease. Herein, we discovered an endogenous PCSK9 binding partner by Far Western blotting, co-immunoprecipitation, and pull-down assays. Following two-dimensional gel electrophoresis and mass spectrometry analysis, we demonstrated that PCSK9 binds to a ∼33-kDa protein identified as annexin A2 (AnxA2) but not to the closely related annexin A1. Furthermore, our functional LDLR assays and small hairpin RNA studies show that AnxA2 and the AnxA2·p11 complex could prevent PCSK9-directed LDLR degradation in HuH7, HepG2, and Chinese hamster ovary cells. Immunocytochemistry revealed that PCSK9 and AnxA2 co-localize at the cell surface, indicating a possible competition with the LDLR. Structure-function analyses demonstrated that the C-terminal cysteine-histidine-rich domain of PCSK9 interacts specifically with the N-terminal repeat R1 of AnxA2. Mutational analysis of this 70-amino acid-long repeat indicated that the RRTKK81 sequence of AnxA2 is implicated in this binding because its mutation to AATAA81 prevents its interaction with PCSK9. To our knowledge, this work constitutes the first to show that PCSK9 activity on LDLR can be regulated by an endogenous inhibitor. The identification of the minimal inhibitory sequence of AnxA2 should pave the way toward the development of PCSK9 inhibitory lead molecules for the treatment of hypercholesterolemia. The proprotein convertase subtilisin kexin-like 9 (PCSK9) 4The abbreviations used are: PCSK9, proprotein convertase subtilisin kexin-like 9; aa, amino acid(s); mAb, monoclonal antibody; AnxA2; annexin A2; AnxA1, annexin A1; CHRD, cysteine-histidine-rich domain; PC, proprotein convertase; LDLR, low density lipoprotein receptor; VLDLR, very low density lipoprotein receptor; shRNA, small hairpin RNA; CHO, Chinese hamster ovary; EGFP, enhanced green fluorescent protein; HA, hemagglutinin; HRP, horseradish peroxidase; CHAPS, 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid; IPG, immobilized pH gradient; MS/MS, tandem mass spectrometry; PBS, phosphate-buffered saline. is the ninth member of a family of secretory serine proteinases known as the proprotein convertases (PCs) (1Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 928-933Crossref PubMed Scopus (934) Google Scholar, 2Seidah N.G. Mayer G. Zaid A. Rousselet E. Nassoury N. Poirier S. Essalmani R. Prat A. Int. J. Biochem. Cell Biol. 2008; 40: 1111-1125Crossref PubMed Scopus (280) Google Scholar). It is now recognized as a major candidate gene for the development of pharmacologically relevant inhibitors or silencers, because it induces an enhanced cellular degradation of the low density lipoprotein receptor (LDLR) in endosomes-lysosomes (3Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, 4Maxwell K.N. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7100-7105Crossref PubMed Scopus (514) Google Scholar). 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Marcinkiewicz J. A. Hamelin J. M. Jin W. J. Seidah N.G. Prat A. 2008; PubMed Scopus Google Scholar). Following PCSK9 the with its and is (1Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 928-933Crossref PubMed Scopus (934) Google Scholar). can be cell binding in an N. Tebon Benjannet S. Hamelin J. Attie A.D. Prat A. Seidah N.G. PubMed Scopus Google and is to the cell LDLR J. PubMed Scopus Google Scholar). PCSK9 may the J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, K.N. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). PCSK9 with LDLR in and N. Tebon Benjannet S. Hamelin J. Attie A.D. Prat A. Seidah N.G. PubMed Scopus Google Scholar). It demonstrated that the C-terminal domain and the of PCSK9 for the of PCSK9 and the LDLR N. Tebon Benjannet S. Hamelin J. Attie A.D. Prat A. Seidah N.G. PubMed Scopus Google Scholar). The is an complex in the (1Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 928-933Crossref PubMed Scopus (934) Google Scholar, S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google and the PCSK9 known is PCSK9 is the that is as a complex (1Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 928-933Crossref PubMed Scopus (934) Google Scholar, S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, M.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the enhanced degradation of the LDLR (3Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, 4Maxwell K.N. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7100-7105Crossref PubMed Scopus (514) Google Scholar, J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google very low density lipoprotein receptor and S. Mayer G. Benjannet S. E. Marcinkiewicz J. Nassoury N. Mayer J. Prat A. Seidah N.G. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google in N. Tebon Benjannet S. Hamelin J. Attie A.D. Prat A. Seidah N.G. PubMed Scopus Google by PCSK9 not to its activity M.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. R. G. G. D. J.L. Biochem. J. PubMed Scopus Google Scholar). in the of this convertase is by the of PCSK9, which revealed an binding complex of the and its inhibitory D. M.C. J.L. S. D. Biol. PubMed Scopus Google Scholar). complex binds the domain of the LDLR R. M. J.C. Hobbs H.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google with at to of D. M.C. J.L. S. D. Biol. PubMed Scopus Google leading to its degradation by The in a PCSK9 to the of of on the identification of of the interaction M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar). on the of the interaction may be mutations of PCSK9 in result in or N.G. Prat A. J. Med. PubMed Scopus Google not implicated in the interaction of the domain with the domain M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar). the and as as the and in or of of PCSK9, M. Varret M. Allard D. M. C. Benjannet S. Wickham L. D. A. L. M. E. J. G. J. Prat A. M. C. Seidah N.G. Boileau C. 2003; PubMed Scopus Google Scholar, N.G. Prat A. J. Med. PubMed Scopus Google Scholar, J. J.L. G. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. A. J.C. Hobbs H.H. J. Full Text Full Text PDF PubMed Scopus Google Scholar). It possible that endogenous of PCSK9 on LDLR may which could specifically with the the or the we a Far Western to a in cell analysis revealed that a protein in and that it interacts specifically with the CHRD, in a of of PCSK9 to the degradation of LDLR. Herein, we the identification and of this endogenous PCSK9 as as its domain that interacts with the PCSK9 and and with or a C-terminal as (3Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, S. Rhainds D. Hamelin J. Nassoury N. Seidah N.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The for N. Basak A. Chretien M. Seidah N.G. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google and (3Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google The for by of of annexin A2 (AnxA2) and annexin and An by at the of and AnxA2. of the used in the AnxA2 in on AnxA2 to mutations and or amino and the AnxA2 with the with the and the of the by RNA a The a analysis of RNA as A. A. Essalmani R. Marcinkiewicz J. A. Hamelin J. M. Jin W. J. Seidah N.G. Prat A. 2008; PubMed Scopus Google Scholar, G. A. J. Seidah N.G. L. Prat A. Biol. 2004; PubMed Scopus Google Scholar). to one for the protein gene for and for and the for the gene of in The used to and the or as G. A. J. Seidah N.G. L. Prat A. Biol. 2004; PubMed Scopus Google Scholar). Cell and HuH7, and cell in with and that G. Hamelin J. Asselin M.C. A. Marcinkiewicz E. M. S. Seidah N.G. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google in with in with and of the at and with with and with the and in or not as indicated in the for an and cell analysis of the AnxA2 in the and for in of the of in and PCSK9 as N. Tebon Benjannet S. Hamelin J. Attie A.D. Prat A. Seidah N.G. 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PubMed Scopus Google used of cell with the of and Following with an revealed a ∼33-kDa protein with in and cell we show that the of with an or proprotein convertase G. Hamelin J. Asselin M.C. A. Marcinkiewicz E. M. S. Seidah N.G. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google not protein that the ∼33-kDa protein specifically binds PCSK9. of revealed that the ∼33-kDa binding protein is with and it is in the and the revealed that a ∼33-kDa PCSK9 is in the small and but is in and in that in the major protein with an mass of small To the we cell with PCSK9 and The that the domain of PCSK9 is its C-terminal CHRD, because a it not to the ∼33-kDa the binds at the PCSK9 and for this interaction with the protein the CHRD, as in the PCSK9 or the S. Rhainds D. Hamelin J. Nassoury N. Seidah N.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the (1Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 928-933Crossref PubMed Scopus (934) Google or the that binds the LDLR D. M.C. J.L. S. D. Biol. PubMed Scopus Google with the ∼33-kDa protein and not the to the ∼33-kDa in the of the binding by that not the we that the and its prevents the of The ∼33-kDa PCSK9 the PCSK9 we an or in cells. Cell with by and mass spectrometry analysis of the at The of the is in The mass revealed that the ∼33-kDa protein is annexin A2 which protein sequence to AnxA2 Furthermore, this protein is in the but not in that AnxA2 is the PCSK9 To the of the ∼33-kDa we of by two-dimensional by two-dimensional with or to and for Far Western with The with a protein in the Western used to the of the to be for mass analysis tandem analysis revealed with a of to AnxA2. The mass that AnxA2 is the major identified with in cell of the of PCSK9 with that the interaction in cell can be by of AnxA2 in that not this we AnxA2 or as in cells. 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The of the interaction on the of PCSK9 by to with the low of and of small in protein by Western of AnxA2 or with to a in of cell LDLR and with of PCSK9 in the of cell LDLR, as with and of AnxA2 with PCSK9 or the of of AnxA2 LDLR in or of with an or a one in a of as with and a of of the LDLR and the that in endogenous AnxA2 can the degradation of the LDLR. of PCSK9 as with or with AnxA2 or with or or with of the of endogenous LDLR in cells. result the AnxA2 and PCSK9 in LDLR of with the revealed that of AnxA2 show to LDLR, the is in AnxA2 because of of AnxA2. result of of the R1 of AnxA2 as the the of AnxA2 that the interaction with PCSK9, we of AnxA2 and in cells. Far Western of cell revealed that of the N-terminal of which is known to be for binding to and and to as G. PubMed Scopus Google Scholar, M. M. J. J. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google not binding to PCSK9 of the first repeat R1 of AnxA2 the interaction with and or of the and major and the R1 repeat to be the major domain of AnxA2 implicated in PCSK9 of the of the R1 domain of AnxA2 and not indicated of of the AnxA2 sequence with the sequence on PCSK9 binding the sequence to or Far Western that the of the sequence is for the binding the sequence by binding of AnxA2 to PCSK9 the mutation of by not this may that the is of the and of AnxA2 by the one of binding to PCSK9 the interaction of PCSK9 with the R1 domain of AnxA2 may be one for The of LDLR and and J.L. Biochem. PubMed Scopus Google Scholar, J.L. PubMed Scopus Google Scholar, J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the of PCSK9 (1Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 928-933Crossref PubMed Scopus (934) Google the of LDLR degradation (3Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. Trillard M. Abifadel M. Tebon A. Attie A.D. Rader D.J. Boileau C. Brissette L. Chretien M. Prat A. Seidah N.G. J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, 4Maxwell K.N. Breslow J.L. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7100-7105Crossref PubMed Scopus (514) Google Scholar, M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar, J.C. Hobbs H.H. Biochem. Sci. Full Text Full Text PDF PubMed Scopus Google is The is that the in interaction of the complex with the domain of the LDLR the of this its degradation by M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar, J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). by the domain the interaction the of PCSK9, and the M.C. J. Proc. 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Cell Sci. PubMed Google Scholar). AnxA2 a but identified on the of cell The this is not known but is on of and of AnxA2 and to PubMed Scopus Google Scholar, M. Cell PubMed Scopus Google Scholar, G. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). The of AnxA2 on the of the plasma demonstrated in J. Biol. Chem. Full Text PDF PubMed Google D.J. H.H. J. Cell Sci. PubMed Google J. Cell Biol. PubMed Scopus Google Scholar, J. PubMed Scopus Google and PubMed Scopus Google Scholar). AnxA2 as a receptor for a of interaction with on cell is J. PubMed Scopus Google as demonstrated by AnxA2 which in and A. M. R. J. 2004; PubMed Scopus Google Scholar). The in this work revealed that the activity of PCSK9 on LDLR can be by AnxA2 its binding to The and the to the PCSK9 it to with the LDLR its domain D. M.C. J.L. S. D. Biol. PubMed Scopus Google Scholar, M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar). we that binding of AnxA2 to the cause in the of PCSK9, its to the degradation of the LDLR. revealed that at AnxA2 the level of cell PCSK9 a to LDLR. of AnxA2 the cell of the LDLR in the complex is in the interaction prevents the of the complex is not Furthermore, it is to be PCSK9 with its binding to as it it binds the LDLR M.C. J. Proc. Natl. Acad. Sci. U. S. A. 2008; PubMed Scopus Google Scholar). of the of AnxA2 in by revealed that it is in with one of the PCSK9 in to in of AnxA2 in cells. AnxA2 protein is in in with the Far Western analysis on revealed that PCSK9 is in and A. A. Essalmani R. Marcinkiewicz J. A. Hamelin J. M. Jin W. J. Seidah N.G. Prat A. 2008; PubMed Scopus Google Scholar). not a AnxA2 in the of the small that the PCSK9 and very low in the of PCSK9 with the interaction of PCSK9 with a ∼33-kDa protein in AnxA2 is very at the of of small and may the of of PCSK9 to the LDLR in A. M.C. J. 2008; Full Text Full Text PDF PubMed Scopus Google as as the of PCSK9, which is in on the of the LDLR A. M.C. J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the PCSK9 is in the LDLR in this not the that may with PCSK9, as by the protein by Far Western The of PCSK9 to the LDLR in and R. M. J.C. Hobbs H.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google may be to of AnxA2 L. J. A. PubMed Scopus Google Scholar). is the first on the of an endogenous of PCSK9. demonstrated the of the of PCSK9 with for a that the LDLR To our knowledge, the binding of a protein to the AnxA2 R1 domain not Furthermore, the identification of the R1 domain of AnxA2 that binding to PCSK9 a to PCSK9 or of this could be used to PCSK9 on LDLR and on as or S. Mayer G. Benjannet S. E. Marcinkiewicz J. Nassoury N. Mayer J. Prat A. Seidah N.G. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). The could be used to a to the implicated in this interaction The is of and and D. M.C. J.L. S. D. Biol. PubMed Scopus Google Scholar). The is in an the and is to the D. M.C. J.L. S. D. Biol. PubMed Scopus Google Scholar). It that the a possible that to the J. J.L. G. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google which not with AnxA2 as by Far it with PCSK9 for binding to AnxA2 The interaction of the R1 domain of AnxA2 with the of the J. J.L. G. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google or a The of AnxA2 on LDL cholesterol to be in studies AnxA2 A. M. R. J. 2004; PubMed Scopus Google would be in this our for a way to the activity of PCSK9 on the LDLR AnxA2 the way to the identification of that may its in a may to the level of circulating LDL cholesterol and the development of coronary heart disease. to and for to Prat for the for the and for analysis, for the and and for PCSK9. to of the Seidah for and to for with
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