Dynamic clustering of dynamin-amphiphysin helices regulates membrane constriction and fission coupled with GTP hydrolysis

摘要

The nerve cells that make up a nervous system connect at junctions known as synapses. When a nerve impulse reaches the end of the cell, membrane-bound packages called vesicles fuse with the surface membrane and release their contents to the outside. The contents, namely chemicals called neurotransmitters, then travels across the synapse, relaying the signal to the next cell. Nerve cells can fire many times per second. The membrane from fused vesicles must be retrieved from the surface membrane and recycled to make new vesicles, ready to transmit more signals across the synapse. Many proteins at these sites are involved in folding the fused membrane back into the cell, constricting the opening, and eventually pinching off the new vesicles – a process known as endocytosis. Two proteins named dynamin and amphiphysin cooperate in this process, but their precise mechanism remained elusive. Dynamin is a protein that acts like a motor; it breaks down a molecule called GTP to release energy. Previous studies have seen that dynamin-amphiphysin complexes join end to end to form long helical structures. Takeda et al. have now looked at how the structure of the helices changes during endocytosis. This revealed that the dynamin-amphiphysin helices rearrange to form clusters when the GTP is broken down. Further analysis showed that the folded membrane becomes constricted at regions that are not coated with the clusters of dynamin-amphiphysin helices. Takeda et al. also discovered that amphiphysin controls the size of the clusters to help make the new vesicles more uniform. The gene for dynamin is altered in a number of disorders affecting the nervous system and muscles, including epileptic encephalopathy, Charcot-Marie-Tooth disease and congenital myopathy. Moreover, a neurological disorder characterized by muscle stiffness (known as Stiff-person syndrome) occurs when an individual’s immune system mistakenly attacks the amphiphysin protein. As such, these new findings will not only help scientists to better understand the process of endocytosis, but they will also give new insight into a number of human diseases.