Science：“人造”多肽探测细胞膜蛋白

生物谷

图片说明：科学家画出的细胞外基质受体糖蛋白，一种跨膜蛋白。红色表示ß亚基，蓝色表示α亚基和较小的人造多肽。

    蛋白质是生物体的重要组成部分，大约有三分之一的蛋白质是存在于细胞膜中的膜蛋白。科学家很容易利用抗体等对其他三分之二的蛋白质进行研究，但对于膜蛋白，情况就要复杂得多。

    为了探测这些似乎“无法接近”的蛋白质，美国宾西法尼亚大学（University  of  Pennsylvania）医学院的研究人员利用计算机技术和已知的蛋白质结构信息，设计制造出一些多肽，它们能够“绑定”相关跨膜蛋白（transmembrane  protein）的特定区域，从而使科学家研究了细胞外基质受体糖蛋白（integrin）对凝血过程第一步的影响机制。该研究成果发表在3月30日《科学》杂志上。

    科学家集中研究了两种名为αIIbß3和αvß3的细胞外基质受体糖蛋白，它们都是会影响凝血时血小板作用的跨膜蛋白。论文高级作者之一、医学教授Joel  Bennett表示，“我们想看看利用两种不同的多肽能否区分出这两种跨膜蛋白分别的作用……事实上，我们做到了。”

    当设计出的多肽被插入血小板细胞膜后，它们与对应细胞外基质受体糖蛋白的部分区域结合，并对其在凝血过程中的官能产生扰动，从而使科学家能够找到人体调控膜蛋白导致凝血的机制。

    Bennett表示，将这种方法用于治疗研究还有很长的路要走，但是科学家可以借此了解人体内最基本的相互作用——细胞协作产生必需功能的方式。而这些知识无疑将成为未来新的靶向药物开发的基础。

部分英文原文：

Science 30 March 2007:
Vol. 315. no. 5820, pp. 1817 - 1822
DOI: 10.1126/science.1136782

Research Articles

Computational Design of Peptides That Target Transmembrane Helices

Hang Yin,1* Joanna S. Slusky,1* Bryan W. Berger,1 Robin S. Walters,1 Gaston Vilaire,2 Rustem I. Litvinov,3 James D. Lear,1 Gregory A. Caputo,1 Joel S. Bennett,2 William F. DeGrado1,4 {dagger}

A variety of methods exist for the design or selection of antibodies and other proteins that recognize the water-soluble regions of proteins; however, companion methods for targeting transmembrane (TM) regions are not available. Here, we describe a method for the computational design of peptides that target TM helices in a sequence-specific manner. To illustrate the method, peptides were designed that specifically recognize the TM helices of two closely related integrins ( {alpha} IIbß3 and {alpha} vß3) in micelles, bacterial membranes, and mammalian cells. These data show that sequence-specific recognition of helices in TM proteins can be achieved through optimization of the geometric complementarity of the target-host complex.

1 Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Hematology-Oncology Division, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4 Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: wdegrado@mail.med.upenn.edu