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胶原蛋白和一种源自矛头蝮蛇毒溶血素的解整合素肽与整合素α2-I结构域的竞争性相互作用。

Competitive interactions of collagen and a jararhagin-derived disintegrin peptide with the integrin alpha2-I domain.

作者信息

Lambert Lester J, Bobkov Andrey A, Smith Jeffrey W, Marassi Francesca M

机构信息

Burnham Institute for Medical Research, La Jolla, California 92037, USA.

出版信息

J Biol Chem. 2008 Jun 13;283(24):16665-72. doi: 10.1074/jbc.M710483200. Epub 2008 Apr 16.

Abstract

Integrin alpha2beta1 is a major receptor required for activation and adhesion of platelets, through the specific recognition of collagen by the alpha2-I domain (alpha2-I), which binds fibrillar collagen via Mg(2+)-bridged interactions. The crystal structure of a truncated form of the alpha2-I domain, bound to a triple helical collagen peptide, revealed conformational changes suggestive of a mechanism where the ligand-bound I domain can initiate and propagate conformational change to the full integrin complex. Collagen binding by alpha2-I and fibrinogen-dependent platelet activity can be inhibited by snake venom polypeptides. Here we describe the inhibitory effect of a short cyclic peptide derived from the snake toxin metalloprotease jararhagin, with specific amino acid sequence RKKH, on the ability of alpha2-I to bind triple helical collagen. Isothermal titration calorimetry measurements showed that the interactions of alpha2-I with collagen or RKKH peptide have similar affinities, and NMR chemical shift mapping experiments with (15)N-labeled alpha2-I, and unlabeled RKKH peptide, indicate that the peptide competes for the collagen-binding site of alpha2-I but does not induce a large scale conformational rearrangement of the I domain.

摘要

整合素α2β1是血小板激活和黏附所需的主要受体,通过α2-I结构域(α2-I)对胶原蛋白的特异性识别来实现,该结构域通过Mg(2+)桥连相互作用与纤维状胶原蛋白结合。与三螺旋胶原肽结合的截短形式α2-I结构域的晶体结构显示出构象变化,提示了一种机制,即配体结合的I结构域可引发并将构象变化传播至完整的整合素复合物。α2-I与胶原蛋白的结合以及纤维蛋白原依赖性血小板活性可被蛇毒多肽抑制。在此,我们描述了一种源自蛇毒素金属蛋白酶矛头蝮蛇毒素(jararhagin)的短环肽(特定氨基酸序列为RKKH)对α2-I结合三螺旋胶原蛋白能力的抑制作用。等温滴定量热法测量表明,α2-I与胶原蛋白或RKKH肽的相互作用具有相似的亲和力,并且用(15)N标记的α2-I和未标记的RKKH肽进行的核磁共振化学位移映射实验表明,该肽竞争α2-I的胶原蛋白结合位点,但不会诱导I结构域发生大规模构象重排。

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