Lee Stephen S J, Knott Vroni, Jovanović Jelena, Harlos Karl, Grimes Jonathan M, Choulier Laurence, Mardon Helen J, Stuart David I, Handford Penny A
The Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Structure. 2004 Apr;12(4):717-29. doi: 10.1016/j.str.2004.02.023.
Human fibrillin-1, the major structural protein of extracellular matrix (ECM) 10-12 nm microfibrils, is dominated by 43 calcium binding epidermal growth factor-like (cbEGF) and 7 transforming growth factor beta binding protein-like (TB) domains. Crystal structures reveal the integrin binding cbEGF22-TB4-cbEGF23 fragment of human fibrillin-1 to be a Ca(2+)-rigidified tetragonal pyramid. We suggest that other cbEGF-TB pairs within the fibrillins may adopt a similar orientation to cbEGF22-TB4. In addition, we have located a flexible RGD integrin binding loop within TB4. Modeling, cell attachment and spreading assays, immunocytochemistry, and surface plasmon resonance indicate that cbEGF22 bound to TB4 is a requirement for integrin activation and provide insight into the molecular basis of the fibrillin-1 interaction with alphaVbeta3. In light of our data, we propose a novel model for the assembly of the fibrillin microfibril and a mechanism to explain its extensibility.
人原纤维蛋白-1是细胞外基质（ECM）10 - 12纳米微原纤维的主要结构蛋白，由43个钙结合表皮生长因子样（cbEGF）结构域和7个转化生长因子β结合蛋白样（TB）结构域组成。晶体结构显示，人原纤维蛋白-1的整合素结合cbEGF22 - TB4 - cbEGF23片段是一个Ca(2+)刚性化的四方锥体。我们认为，原纤维蛋白内的其他cbEGF - TB对可能采用与cbEGF22 - TB4相似的取向。此外，我们在TB4内定位了一个灵活的RGD整合素结合环。建模、细胞附着和铺展试验、免疫细胞化学以及表面等离子体共振表明，与TB4结合的cbEGF22是整合素激活的必要条件，并深入了解了原纤维蛋白-1与αVβ3相互作用的分子基础。根据我们的数据，我们提出了一种原纤维蛋白微原纤维组装的新模型以及一种解释其可扩展性的机制。
