PDF(Pubmed)
Abstract：
Focal adhesions (FAs) mediate the interaction of the cytoskeleton with the extracellular matrix in a highly dynamic fashion. Talin is a central regulator, adaptor protein, and mechano-sensor of FA complexes. For recruitment and firm attachment at FAs, talin\'s N-terminal FERM domain binds to phosphatidylinositol 4,5-bisphosphate (PIP2)-enriched membranes. A newly published autoinhibitory structure of talin-1, where the known PIP2 interaction sites are covered up, lead us to hypothesize that a hitherto less examined loop insertion of the FERM domain acts as an additional and initial site of contact. We evaluated direct interactions of talin-1 with a PIP2 membrane by means of atomistic molecular dynamics simulations. We show that this unstructured, 33-residue-long loop strongly interacts with PIP2 and can facilitate further membrane contacts, including the canonical PIP2 interactions, by serving as a flexible membrane anchor. Under force as present at FAs, the extensible FERM loop ensures talin maintains membrane contacts when pulled away from the membrane by up to 7 nm. We identify key basic residues of the anchor mediating the highly dynamic talin-membrane interaction. Our results put forward an intrinsically disordered loop as a key and highly adaptable PIP2 recognition site of talin and potentially other PIP2-binding mechano-proteins.
摘要：
粘着斑（FA）以高度动态的方式介导细胞骨架与细胞外基质（ECM）的相互作用。塔林是一个中央调节器，衔接蛋白和粘着斑复合物的机械传感器。对于FAs的招聘和公司依恋，talin的N端FERM结构域与富含磷脂酰肌醇4,5-二磷酸（PIP2）的膜结合。一种新发表的talin-1的自抑制结构，其中已知的PIP2相互作用位点被掩盖，引导我们假设迄今为止较少被检查的FERM结构域的环插入充当额外的初始接触位点。我们通过原子分子动力学（MD）模拟评估了talin-1与PIP2膜的直接相互作用。我们证明了这种非结构化的，33个残基长的回路与PIP2强烈相互作用，可以促进进一步的膜接触，包括规范的PIP2相互作用，作为一个灵活的膜锚。在FA存在的力量下，可延伸的FERM环确保talin保持膜接触时，拉离膜达7nm。我们确定了介导高度动态的滑石-膜相互作用的锚的关键基本残基。我们的结果提出了一个内在无序的环，作为talin和潜在的其他PIP2结合机制蛋白的关键和高度适应性的PIP2识别位点。
