Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
PLoS One. 2009 Dec 30;4(12):e8295. doi: 10.1371/journal.pone.0008295.
Formation, degradation and renewal of cellular organelles is a dynamic process based on permanent budding, fusion and inter-organelle traffic of vesicles. These processes include many regulatory proteins such as SNAREs, Rabs and coats. Given this complex machinery, a controversially debated issue is the definition of a minimal set of generic mechanisms necessary to enable the self-organization of organelles differing in number, size and chemical composition. We present a conceptual mathematical model of dynamic organelle formation based on interacting vesicles which carry different types of fusogenic proteins (FP) playing the role of characteristic marker proteins. Our simulations (ODEs) show that a de novo formation of non-identical organelles, each accumulating a different type of FP, requires a certain degree of disproportionation of FPs during budding. More importantly however, the fusion kinetics must indispensably exhibit positive cooperativity among these FPs, particularly for the formation of larger organelles. We compared different types of cooperativity: sequential alignment of corresponding FPs on opposite vesicle/organelles during fusion and pre-formation of FP-aggregates (equivalent, e.g., to SNARE clusters) prior to fusion described by Hill kinetics. This showed that the average organelle size in the system is much more sensitive to the disproportionation strength of FPs during budding if the vesicular transport system gets along with a fusion mechanism based on sequential alignments of FPs. Therefore, pre-formation of FP aggregates within the membranes prior to fusion introduce robustness with respect to organelle size. Our findings provide a plausible explanation for the evolution of a relatively large number of molecules to confer specificity on the fusion machinery compared to the relatively small number involved in the budding process. Moreover, we could speculate that a specific cooperativity which may be described by Hill kinetics (aggregates or Rab/SNARE complex formation) is suitable if maturation/identity switching of organelles play a role (bistability).
细胞细胞器的形成、降解和更新是一个基于囊泡不断出芽、融合和细胞器间运输的动态过程。这些过程包括许多调节蛋白，如 SNAREs、Rabs 和衣被蛋白。考虑到这个复杂的机制，一个有争议的问题是定义一套最小的通用机制，使数量、大小和化学组成不同的细胞器能够自我组织。我们提出了一个基于相互作用的囊泡的动态细胞器形成的概念数学模型，这些囊泡携带不同类型的融合蛋白（FP），起到特征标记蛋白的作用。我们的模拟（ODE）表明，非同源细胞器的从头形成，每个细胞器积累不同类型的 FP，需要在出芽过程中 FP 发生一定程度的不成比例分配。然而，更重要的是，融合动力学必须在这些 FP 之间表现出正协同作用，特别是对于较大细胞器的形成。我们比较了不同类型的协同作用：在融合过程中对应 FP 在相对囊泡/细胞器上的顺序排列，以及融合前 FP 聚集物（例如，类似于 SNARE 簇）的形成，由 Hill 动力学描述。这表明，如果囊泡运输系统与基于 FP 顺序排列的融合机制相适应，那么在出芽过程中 FP 不成比例分配对系统中平均细胞器大小的影响要大得多。因此，在融合之前，在膜内形成 FP 聚集物可以提高细胞器大小的稳健性。我们的研究结果为融合机制中涉及的分子数量相对较少而特异性赋予融合机制的进化提供了一个合理的解释。此外，我们可以推测，如果细胞器的成熟/身份转换起作用（双稳定性），那么可能由 Hill 动力学（聚集物或 Rab/SNARE 复合物形成）描述的特定协同作用是合适的。
