Kranenburg Onno, Bouma Barend, Kroon-Batenburg Loes M J, Reijerkerk Arie, Wu Ya-Ping, Voest Emile E, Gebbink Martijn F B G
Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Curr Biol. 2002 Oct 29;12(21):1833-9. doi: 10.1016/s0960-9822(02)01224-1.
Tissue-type plasminogen activator (tPA) regulates fibrin clot lysis by stimulating the conversion of plasminogen into the active protease plasmin. Fibrin is required for efficient tPA-mediated plasmin generation and thereby stimulates its own proteolysis. Several fibrin regions can bind to tPA, but the structural basis for this interaction is unknown. Amyloid beta (Abeta) is a peptide aggregate that is associated with neurotoxicity in brains afflicted with Alzheimer's disease. Like fibrin, it stimulates tPA-mediated plasmin formation. Intermolecular stacking of peptide backbones in beta sheet conformation underlies cross-beta structure in amyloid peptides. We show here that fibrin-derived peptides adopt cross-beta structure and form amyloid fibers. This correlates with tPA binding and stimulation of tPA-mediated plasminogen activation. Prototype amyloid peptides, including Abeta and islet amyloid polypeptide (IAPP) (associated with pancreatic beta cell toxicity in type II diabetes), have no sequence similarity to the fibrin peptides but also bind to tPA and can substitute for fibrin in plasminogen activation by tPA. Moreover, the induction of cross-beta structure in an otherwise globular protein (endostatin) endows it with tPA-activating potential. Our results classify tPA as a multiligand receptor and show that cross-beta structure is the common denominator in tPA binding ligands.
组织型纤溶酶原激活剂（tPA）通过刺激纤溶酶原转化为活性蛋白酶纤溶酶来调节纤维蛋白凝块的溶解。纤维蛋白是tPA介导的纤溶酶生成所必需的，因此会刺激自身的蛋白水解。纤维蛋白的几个区域可以与tPA结合，但其相互作用的结构基础尚不清楚。β淀粉样蛋白（Aβ）是一种肽聚集体，与患有阿尔茨海默病的大脑中的神经毒性有关。与纤维蛋白一样，它也能刺激tPA介导的纤溶酶形成。β折叠构象中肽主链的分子间堆积是淀粉样肽中交叉β结构的基础。我们在此表明，纤维蛋白衍生肽会形成交叉β结构并形成淀粉样纤维。这与tPA结合以及tPA介导的纤溶酶原激活的刺激相关。包括Aβ和胰岛淀粉样多肽（IAPP）（与II型糖尿病中的胰腺β细胞毒性有关）在内的原型淀粉样肽与纤维蛋白肽没有序列相似性，但也能与tPA结合，并可在tPA介导的纤溶酶原激活中替代纤维蛋白。此外，在原本呈球状的蛋白（内皮抑素）中诱导交叉β结构赋予了它tPA激活潜力。我们的结果将tPA归类为多配体受体，并表明交叉β结构是tPA结合配体的共同特征。
