tailieunhanh - Báo cáo khoa học: Oligomerization is required for the activity of recombinant soluble LOX-1

LOX-1 is a scavenger receptor that functions as the primary receptor for oxidized low-density lipoprotein (OxLDL) in endothelial cells. The binding of OxLDL to LOX-1 is believed to lead to endothelial activation, dysfunc-tion, and injury, which constitute early atherogenic events. Because of its potential pathological role in atherosclerosis, LOX-1 has been proposed as a therapeutic target for the treatment of this disease. | ỊFEBS Journal Oligomerization is required for the activity of recombinant soluble LOX-1 XAMi c yao1 ya sri a c ya l ea l-t N 1 A H o Root1 yara1 l hptpmpnpp I am1 .Qtpnhpnp fXllanrl1 vve vau V alcllc kzdld UIU MUalll nuui JldUC I dll Ixl Icicl lienee Ldl II o Lcpildllc J I lai IU Jocelyn Sanford1 Angela Robdk1 Richard Zollner1 Zhijian Lu1 Mostdfd Ait-Zdhra1 Rita Agostinelli1 Lioudmila Tchistiakova1 Davinder Gill1 Douglas Harnish2 Janet Paulsen1 and Heather H. Shih1 1 Department of BiologicalTechnologies Wyeth Research Cambridge MA USA 2 Department of Metabolic Diseases Wyeth Research Cambridge MA USA Keywords Fc fusion protein LOX-1 receptor oligomerization recombinant protein scavenger receptor Correspondence H. H. Shih Department of Biological Technologies Wyeth Research 87 Cambridge Park Drive Cambridge MA 02140 USA Fax 1 617 665 8350 Tel 1 617 665 7473 E-mail hshih@ These authors contributed equally to this work Received 30 January 2009 revised 31 May 2009 accepted 1 July 2009 doi LOX-1 is a scavenger receptor that functions as the primary receptor for oxidized low-density lipoprotein OxLDL in endothelial cells. The binding of OxLDL to LOX-1 is believed to lead to endothelial activation dysfunction and injury which constitute early atherogenic events. Because of its potential pathological role in atherosclerosis LOX-1 has been proposed as a therapeutic target for the treatment of this disease. In order to antagonize the ligand-binding function of cell surface LOX-1 we generated a series of recombinant human LOX-1-crystallizable fragment Fc fusion proteins and subsequently characterized their biochemical properties and ligandbinding activities in vitro. Consistent with the notion that oligomerization of cell surface LOX-1 is required for high-avidity binding of ligands we found that LOX-1-Fc fusion protein containing four ligand-binding domains per Fc dimer but not the one containing two ligand-binding domains exhibited

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