Gao Mu, Craig David, Lequin Olivier, Campbell Iain D, Vogel Viola, Schulten Klaus
Beckman Institute and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14784-9. doi: 10.1073/pnas.2334390100. Epub 2003 Dec 1.
Fibronectin (FN) forms fibrillar networks coupling cells to the extracellular matrix. The formation of FN fibrils, fibrillogenesis, is a tightly regulated process involving the exposure of cryptic binding sites in individual FN type III (FN-III) repeats presumably exposed by mechanical tension. The FN-III1 module has been previously proposed to contain such cryptic sites that promote the assembly of extracellular matrix FN fibrils. We have combined NMR and steered molecular dynamics simulations to study the structure and mechanical unfolding pathway of FN-III1. This study finds that FN-III1 consists of a beta-sandwich structure that unfolds to a mechanically stable intermediate about four times the length of the native folded state. Considering previous experimental findings, our studies provide a structural model by which mechanical stretching of FN-III1 may induce fibrillogenesis through this partially unfolded intermediate.
纤连蛋白（FN）形成将细胞与细胞外基质相连的纤维状网络。FN纤维的形成，即纤维形成过程，是一个受到严格调控的过程，涉及到单个III型FN（FN-III）重复序列中隐蔽结合位点的暴露，推测这些位点是由机械张力暴露的。先前有人提出FN-III1模块包含促进细胞外基质FN纤维组装的此类隐蔽位点。我们结合了核磁共振（NMR）和定向分子动力学模拟来研究FN-III1的结构和机械展开途径。这项研究发现，FN-III1由一个β-三明治结构组成，该结构展开形成一个机械稳定的中间体，其长度约为天然折叠状态的四倍。考虑到先前的实验结果，我们的研究提供了一个结构模型，通过该模型，FN-III1的机械拉伸可能通过这个部分展开的中间体诱导纤维形成。
