Nobel Prize in Physiology or Medicine Awarded for Vesicle Trafficking
October 7, 2013
James E. Rothman, Randy W. Schekman and Thomas C. Südhof received a pleasant call this morning. The scientists were told they were the recipients of the 2013 Nobel Prize in Physiology or Medicine. Their scientific careers explored the mechanism of how vesicles traffic inside the cell, what facilitates this transport, and how the vesicles merge with membranes to releases their contents outside.
So, what is vesicle trafficking?
Every cell in your body is surrounded by a semi-permiable membrane, the lipid bilayer. This membrane is what separates your cellular contents from the environment. Without this barrier, many ,if not all, of the processes in the cell could not function. This separation helps control every thing from driving up the ATP to maintaining a voltage gradient. It keeps virus and bacteria outside, and the genes and energy inside.
There are features of the membranes that allow for small molecules to pass through; for instance, channels, pores, pumps let ions, water, and more through. But what about big molecules? How do they get into the cell? The answer is vesicle transport, and more specifically endocytosis.
(The mechanisms can get really detailed so I will refer you to the key molecules.)
For cargo to come into the cell it has to make it past the cell membrane. Rather than opening up and exposing the inside of the cell, the membrane wraps around the content and engulfs it . Like a blanket rising up and covering a ball. This is driven by AP2 and Clathrin, or Caveolae. Now the membrane is surrounding the cargo. It pinches off so that the cargo is in its own membrane bubble, now called a vesicle. The membrane remains sealed.
The cargo has different destinations, there are tags (Rab) that are placed on the vesicle and these mature through stages. These are called Endosomes. There is a multitude of functions that these endosomes can do depending on the cargo inside and the organelle needing the cargo. Some of the endosomes are degraded as well.
Now as you anticipated, vesicle trafficking is not limited to cargo coming in, it also includes cargo being trafficked out, referred to as Secretory pathways. Here the cargo is packaged and needs to leave the cell through a processes called exocytosis. The cargo is wrapped inside a membrane and it fuses with the membrane of the cell to be expelled. While this sounds simple, its not. It takes a huge amount of energy to merge vesicles, it requires wedging their lipids open. This is why they are such good protection for our cells. Well there is a molecule that can do that. SNAREs are able to fuse vesicles.
So there you have it, three ways that vesicles trafficking occurs - through endocytosis, transport, and exocytosis. These function in nearly every cell of your body. Your digestion system, your immune system and your cells during development could not function without these wonderful mechanisms. It is important to understand these mechanisms because some bacteria have hijacked these molecules to gain access to your cells and infect.
The researchers behind the mechanism
According to Yale University’s website, “Rothman reconstituted vesicle budding and fusion in a cell-free system (1984) and discovered the complex of SNARE proteins (1993) which mediates membrane fusion and affords it specificity. He also uncovered the GTPase-switch mechanism which controls coated vesicle budding in the cell (1991).” [x].
Unlike Rothman who used mainly biochemical approaches, Schekman used a genetic approach. They worked independently. However both researchers were able to tease apart the molecular mechanisms of how vesicle form, how cargo is selected, and how the vesicle moves to the correct organelle or outside the cell.
Schekman found 50 genes involved in these mechanisms, and began to make sense of their gene products in a causal chain of events of the mechanisms. According to HHMI’s webpage, “One of the most important genes he found, Schekman says, is the SEC61 gene, which encodes a channel through which secretory proteins under construction pass into the endoplasmic reticulum lumen. When this gene is mutant, proteins fail to enter the secretion assembly line.” [x].
As for Südhof, he worked at on the mechanisms of pre-synaptic vesicle release. When a neuron fires it releases neurotransmitters, chemicals which can signal the next neuron to fire. Südhof, again working independently figured out the mechanism that synaptotagmins, proteins that are sensitive to the calcium of a cell that fires and responds by controlling vesicle fusion. According to the HHMI’s announcement of the Nobel Prize, “He also found RIMs and Munc13s—proteins that help fuse neurotransmitter vesicles to the presynaptic nerve cell membrane and enable the nerve cell to transmit messages more easily. Furthermore, his work identified central components of the presynaptic machinery mediating the fusion of the vesicles with the presynaptic plasma membrane, the process that effects neurotransmitter release and that is controlled by synaptotagmins.” [x].
Südhof’s work did not stop there. He studied other protiens involved in the mechanism in the vesciles as well as some mechanisms on the post synaptic neurons.
Congratulations to Rothman, Schekman and Südhof! Your decades of research has paid off.
Selected readings and viewings: