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Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis.

Nature communications (2018-09-08)
Xiaohong Ruby Xu, Yiming Wang, Reheman Adili, Lining Ju, Christopher M Spring, Joseph Wuxun Jin, Hong Yang, Miguel A D Neves, Pingguo Chen, Yan Yang, Xi Lei, Yunfeng Chen, Reid C Gallant, Miao Xu, Hailong Zhang, Jina Song, Peifeng Ke, Dan Zhang, Naadiya Carrim, Si-Yang Yu, Guangheng Zhu, Yi-Min She, Terry Cyr, Wenbin Fu, Guoqing Liu, Philip W Connelly, Margaret L Rand, Khosrow Adeli, John Freedman, Jeffrey E Lee, Patrick Tso, Patrizia Marchese, W Sean Davidson, Shaun P Jackson, Cheng Zhu, Zaverio M Ruggeri, Heyu Ni
ABSTRACT

Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Maleimide, 99%
Sigma-Aldrich
PAC-1, ≥98% (HPLC)
Sigma-Aldrich
Ala-Tyr-Pro-Gly-Lys-Phe-NH2 trifluoroacetate salt, ≥98% (HPLC), lyophilized powder
Sigma-Aldrich
Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe, ≥97% (HPLC)