Institut Curie and CNRS UMR 144, 26 rue d'Ulm, 75005 Paris, France.
INSERM, UMR1048, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, 1 avenue Jean Poulhès, 31432 Toulouse, France.
Nat Commun. 2014 Dec 9;5:5647. doi: 10.1038/ncomms6647.
Phosphoinositides play a central role in many physiological processes by assisting the recruitment of proteins to membranes through specific phosphoinositide-binding motifs. How this recruitment is coordinated in space and time is not well understood. Here we show that BIN1/M-Amphiphysin2, a protein involved in T-tubule biogenesis in muscle cells and frequently mutated in centronuclear myopathies, clusters PtdIns(4,5)P2 to recruit its downstream partner dynamin. By using several mutants associated with centronuclear myopathies, we find that the N-BAR and the SH3 domains of BIN1 control the kinetics and the accumulation of dynamin on membranes, respectively. We show that phosphoinositide clustering is a mechanism shared by other proteins that interact with PtdIns(4,5)P2, but do not contain a BAR domain. Our numerical simulations point out that clustering is a diffusion-driven process in which phosphoinositide molecules are not sequestered. We propose that this mechanism plays a key role in the recruitment of downstream phosphoinositide-binding proteins.
磷酯酰肌醇在许多生理过程中发挥核心作用，通过特定的磷酯酰肌醇结合基序协助蛋白质向膜的募集。然而，这种募集如何在空间和时间上协调还不是很清楚。在这里，我们表明 BIN1/M-肌球蛋白重链结合蛋白 2，一种参与肌肉细胞 T 小管发生的蛋白质，以及经常在核纤层肌病中发生突变的蛋白质，将 PtdIns(4,5)P2 聚集起来以招募其下游伙伴 dynamin。通过使用几种与核纤层肌病相关的突变体，我们发现 BIN1 的 N-BAR 和 SH3 结构域分别控制 dynamin 在膜上的动力学和积累。我们表明，磷酯酰肌醇的聚集是与 PtdIns(4,5)P2 相互作用但不包含 BAR 结构域的其他蛋白质所共有的机制。我们的数值模拟指出，聚集是一个由扩散驱动的过程，其中磷酯酰肌醇分子不会被隔离。我们提出，这种机制在募集下游的磷酯酰肌醇结合蛋白中起着关键作用。
