Sorting, topology, and structural control in cells

点击翻译按钮获取中文摘要

The Golgi Apparatus, a key organelle in eukaryotic cells, processes and traffics molecules. Modifying proteins/lipids and then distributing them, it is essential to the operation of the cell. It is not surprising then that structural issues in the Golgi are linked to neurodegenerative diseases, cardiovascular disease and cancer, to name but a few. Membrane bound organelles exhibit robust regulatory response; despite supporting a constant flux of molecules the structure of the Golgi is very stable and reforms rapidly if destroyed or after a mitotic event. Yet after a century of research, how this organelle regulates its morphology and function is poorly understood. We will tackle this problem using a physical approach. The Golgi, consisting of the Golgi complex and Trans Golgi Network (TGN), can be modelled as acollection of surfaces with very different topological characteristics. The complex is comprised of many sac-like cisternae- picture a stack of pancakes. It has positive curvature in the sense of the integral of its Gaussian curvature. This is in stark contrast to the very negative curvature of the TGN, a network of cups and tubules with many handles. Our preliminary research provided understanding of how a physical approach could explain the stability of this structure. We will build this into a robust model using a physical description of the membrane energy. Achieving this relies on a background of mathematical knowledge but also benefits from the biological insights that partners in Institut Curie provide, ensuring the theory can be tested against experimental observations. These include, but are not limited to, the up-regulation of vesicular traffic on the Golgi or ER. In our approach we characterise events such as vesiculation, when a small sphere of membrane buds off the Golgi, based on the resulting changes to the free energy of the system. The free energy can be described as the bending energy of the membrane and vesicle, given by an integral form known as the Helfrich Hamiltonian, plus entropy contribution arising from preferential recruitment of surface proteins. These are driven onto the vesicle by a preference for its (highly positive) Gaussian curvature, leaving behind molecules with a higher propensity for negative curvature. By invoking a near-equilibrium approximation we can calculate the vesicle composition that minimises the free energy. We must then embed this into the architecture of a dynamical system representing the supply and removal of membrane. We seek analytical insights and so consider a deterministic system first, which will facilitate the description of the trafficking steady state. The next task is to model deeper levels of complexity until we are accurately describing the real world system.