Moriarty Róisín, McManus Ciara A, Lambert Matthew, Tilley Thea, Devocelle Marc, Brennan Marian, Kerrigan Steven W, Cox Dermot
Dermot Cox, BSc, PhD, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland, Tel.: +35 3 1 402 2152, Fax: +35 3 1 402 2453, E-mail:
Thromb Haemost. 2015 Feb;113(2):290-304. doi: 10.1160/TH14-04-0366. Epub 2014 Nov 20.
The integrin αIIbβ3 on resting platelets can bind to immobilised fibrinogen resulting in platelet spreading and activation but requires activation to bind to soluble fibrinogen. αIIbβ3 is known to interact with the general integrin-recognition motif RGD (arginine-glycine-aspartate) as well as the fibrinogen-specific γ-chain dodecapeptide; however, it is not known how fibrinogen binding triggers platelet activation. NGR (asparagine-glycine-arginine) is another integrin-recognition sequence present in fibrinogen and this study aims to determine if it plays a role in the interaction between fibrinogen and αIIbβ3. NGR-containing peptides inhibited resting platelet adhesion to fibrinogen with an IC50 of 175 µM but failed to inhibit the adhesion of activated platelets to fibrinogen (IC50> 500 µM). Resting platelet adhesion to mutant fibrinogens lacking the NGR sequences was reduced compared to normal fibrinogen under both static and shear conditions (200 s⁻¹). However, pre-activated platelets were able to fully spread on all types of fibrinogen. Thus, the NGR motif in fibrinogen is the site that is primarily responsible for the interaction with resting αIIbβ3 and is responsible for triggering platelet activation.
静息血小板上的整合素αIIbβ3可与固定化纤维蛋白原结合，导致血小板铺展和激活，但需要激活才能与可溶性纤维蛋白原结合。已知αIIbβ3可与一般的整合素识别基序RGD（精氨酸 - 甘氨酸 - 天冬氨酸）以及纤维蛋白原特异性γ链十二肽相互作用；然而，尚不清楚纤维蛋白原结合如何触发血小板激活。NGR（天冬酰胺 - 甘氨酸 - 精氨酸）是纤维蛋白原中存在的另一种整合素识别序列，本研究旨在确定它是否在纤维蛋白原与αIIbβ3的相互作用中发挥作用。含NGR的肽抑制静息血小板与纤维蛋白原的黏附，IC50为175 μM，但未能抑制激活血小板与纤维蛋白原的黏附（IC50> 500 μM）。在静态和剪切条件（200 s⁻¹）下，与正常纤维蛋白原相比，静息血小板与缺乏NGR序列的突变纤维蛋白原的黏附减少。然而，预激活的血小板能够在所有类型的纤维蛋白原上完全铺展。因此，纤维蛋白原中的NGR基序是主要负责与静息αIIbβ3相互作用并触发血小板激活的位点。
