올해 노벨 생리의학상은 제임스 로스먼(63) 미 예일대 화학과교수, 랜디 셰크먼(65) UC버클리 분자생물학과교수, 독일 출신인 토마스 쥐트호프(58) 스탠포드 의대교수 3인이 선정되었다. 스웨덴 카롤린스카 의대 노벨위원회는 7일(현지시간) “세 사람은 세포의 물질 운송 메커니즘을 규명한 공로가 인정된다”고 선정 이유를 밝혔다.
|About the Nobel prize Laureate|
The Nobel Assembly at Karolinska Institutet has today decided to award
The 2013 Nobel Prize in Physiology or Medicine
James E. Rothman, Randy W. Schekman
and Thomas C. Sudhof
for their discoveries of machinery regulating vesicle traffic,
a major transport system in our cells
The 2013 Nobel Prize honours three scientists who have solved the mystery of how the cell organizes its transport system. Each cell is a factory that produces and exports molecules. For instance, insulin is manufactured and released into the blood and chemical signals called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. The three Nobel Laureates have discovered the molecular principles that govern how this cargo is delivered to the right place at the right time in the cell.
Randy Schekman discovered a set of genes that were required for vesicle traffic. James Rothman unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Thomas Sudhof revealed how signals instruct vesicles to release their cargo with precision.
Through their discoveries, Rothman, Schekman and Sudhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.
How cargo is transported in the cell
In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are everything. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. How do these vesicles know where and when to deliver their cargo?
Traffic congestion reveals genetic controllers
Randy Schekman was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman identified three classes of genes that control different facets of the cell´s transport system, thereby providing new insights into the tightly regulated machinery that mediates vesicle transport in the cell.
Docking with precision
James Rothman was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents.
It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery.
Timing is everything
Thomas Sudhof was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium ions were known to be involved in this process and in the 1990s, Sudhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. The zipper opens up and signal substances are released. Sudhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command.
Vesicle transport gives insight into disease processes
The three Nobel Laureates have discovered a fundamental process in cell physiology. These discoveries have had a major impact on our understanding of how cargo is delivered with timing and precision within and outside the cell. Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Defective vesicle transport occurs in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. Without this wonderfully precise organization, the cell would lapse into chaos.
James E. Rothman was born 1950 in Haverhill, Massachusetts, USA. He received his PhD from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University in California, where he started his research on the vesicles of the cell. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University. In 2008, he joined the faculty of Yale University in New Haven, Connecticut, USA, where he is currently Professor and Chairman in the Department of Cell Biology.
Randy W. Schekman was born 1948 in St Paul, Minnesota, USA, studied at the University of California in Los Angeles and at Stanford University, where he obtained his PhD in 1974 under the supervision of Arthur Kornberg (Nobel Prize 1959) and in the same department that Rothman joined a few years later. In 1976, Schekman joined the faculty of the University of California at Berkeley, where he is currently Professor in the Department of Molecular and Cell biology. Schekman is also an investigator of Howard Hughes Medical Institute.
Thomas C. Sudhof was born in 1955 in Gottingen, Germany. He studied at the Georg-August-Universitat in Gottingen, where he received an MD in 1982 and a Doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas, Texas, USA, as a postdoctoral fellow with Michael Brown and Joseph Goldstein (who shared the 1985 Nobel Prize in Physiology or Medicine). Sudhof became an investigator of Howard Hughes Medical Institute in 1991 and was appointed Professor of Molecular and Cellular Physiology at Stanford University in 2008.
Novick P, Schekman R: Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1979; 76:1858-1862.
Balch WE, Dunphy WG, Braell WA, Rothman JE: Reconstitution of the transport of protein between successive compartments of the Golgi measured by the coupled incorporation of N-acetylglucosamine. Cell 1984; 39:405-416.
Kaiser CA, Schekman R: Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway. Cell 1990; 61:723-733.
Perin MS, Fried VA, Mignery GA, Jahn R, Sudhof TC: Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature 1990; 345:260-263.
Sollner T, Whiteheart W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE: SNAP receptor implicated in vesicle targeting and fusion. Nature 1993; 362:318-324.
Hata Y, Slaughter CA, Sudhof TC: Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 1993; 366:347-351.
사진 및 내용 출처: MLA style: "The 2013 Nobel Prize in Physiology or Medicine - Press Release". Nobelprize.org. Nobel Media AB 2013. Web. 7 Oct 2013.
Scientific Background: Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells
|James E Rothman|
Departments & Organizations
Yale Combined Program in the Biological and Biomedical Sciences (BBS): Molecular Cell Biology, Genetics and Development | Biochemistry, Biophysics and Structural Biology
Cell Biology: Membrane Traffic | Rothman Lab
Elucidating the underlying mechanisms of vesicular transport within cells and the secretion of hormones and neurotransmitters more...
- B.A., Yale University, 1971
-Ph.D., Harvard Medical School, 1976
- Kummel, D., Krishnakumar, S.S., Radoff, D.T., Li, F., Giraudo, C.G., Pincet, F., Rothman, J.E., and Reinisch, K.M. 2011. Complexin Cross-links prefusion SNAREs into a Zig-Zag Array. 2011. Nat. Struct. Mol. Biol. 18:927-33.
- Krishnakumar, S.S., Radoff, D.T., Kummel, D, Giraudo,C.G., Li, F., Khandan, L., Baguley, S.W., Coleman, J., Reinisch, K.M., Pincet, F., and Rothman, J.E. "A Conformational Switch in Complexin is Required for Synaptotagmin to Trigger Synaptic Fusion" Nat. Struct. Mol. Biol. (2011) 18, 933-40.
- Li, F., Pincet, F., Perez, E., Giraudo, C.G., Tareste, D., and Rothman, J.E. " Complexin Activates and Clamps SNAREpins by a Common Mechanism Involving an Intermediate Energetic State" Nat. Struct. Mol. Biol. (2011) 18, 941-46.
|Randy W. Schekman|
Biochemistry, Cell Biology
The Schekman Lab...
University of California, Berkeley
Dr. Schekman is also a professor of molecular and cell biology at the University of California, Berkeley, and an adjunct professor of biochemistry and biophysics at the University of California, San Francisco.
Intracellular Transport of Proteins
Randy Schekman's research is focused on the process of membrane assembly, vesicular transport, and membrane fusion among organelles of the secretory pathway.
Read more ?
Traffic inside a cell is as complicated as rush hour near any metropolitan area. But drivers know how to follow the signs and roadways to reach their destinations. How do different cellular proteins "read" molecular signposts to find their way inside or outside of a cell?
For the past three decades, Randy Schekman has been characterizing the traffic drivers that shuttle cellular proteins as they move in membrane-bound sacs, or vesicles, within a cell. His detailed elucidation of cellular travel patterns has provided fundamental knowledge about cells and has enhanced understanding of diseases that arise when bottlenecks impede some of the protein flow.
His work earned him one of the most prestigious prizes in science, the Albert Lasker Award for Basic Medical Research, which he shared with James Rothman in 2002.
Schekman's path to award-winning researcher began with a youthful enthusiasm for science and math, which he attributes to his father, an engineer who helped develop the first online program for real-time stock quotes. High school science fairs?and winning them?further whetted his appetite for competitive science. Biology's power hit him more personally, though, when his teenage sister died of leukemia.
He considered pursuing medical school as an undergraduate at the University of California, Los Angeles. But after spending his junior year in a laboratory at the University of Edinburgh, his path to graduate school became set. He obtained a Ph.D. in biochemistry at Stanford in the laboratory of Arthur Kornberg, who won the Nobel Prize in 1959 for identifying a key enzyme in DNA synthesis.
Schekman first became interested in how proteins move within cells during a postdoctoral fellowship between 1974 and 1976 with John Signer, who was studying the outer membranes of mammalian cells. At the time, though, scientists couldn't easily study the steps of vesicle movement in mammalian cells growing in culture.
So Schekman, who moved in 1976 to the University of California, Berkeley, as an independent investigator, decided to use yeast, a one-celled microorganism, to determine how vesicles containing proteins move inside and outside the cell. Scientists can easily genetically manipulate yeast, which have membrane-bound organelles similar to those of higher organisms. Organelles, such as mitochondria or the Golgi apparatus, are structures within cells that perform specified functions.
When Schekman began his yeast studies, scientists only had a general sense of the cellular traffic patterns that proteins follow: Ribosomes manufacture proteins, which enter the endoplasmic reticulum, a membranous network inside the cell. Vesicles carrying proteins pinch off from the endoplasmic reticulum and travel to the Golgi apparatus, which further processes the proteins for internal or external use.
What Schekman, using genetic methods, and Rothman, with biochemical approaches, working independently did, was dissect in meticulous detail the molecular underpinnings behind vesicle formation, selection of cargo, and movement to the correct organelle or path outside the cell.
Ultimately, he identified 50 genes involved in vesicle movement and determined the order and role each of the different genes' protein products play, step by step, as they shuttle cargo-laden vesicles in the cell. 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.
Another significant set of genes he discovered encode different coat proteins that allow vesicle movement from the endoplasmic reticulum and from the Golgi.
Although Schekman's research was done in yeast, follow-up studies confirmed that higher organisms, such as humans, share the majority of the genes in the yeast secretory pathway. Such knowledge provided a foundation for understanding normal human cell biology and disease states.
In fact, as the study of the genetics of mammalian cells has become easier, Schekman has been characterizing human diseases that arise from secretory pathway problems. He has identified the structural basis of a rare craniofacial disease that disrupts the construction of a coat protein complex essential for transport vesicle formation. He also is studying whether the accumulation in the brains of Alzheimer's disease patients of the protein amyloid is due to a secretion pathway roadblock.
While many steps in vesicular trafficking are now known, some have evaded discovery. Schekman continues to look for receptors in the endoplasmic reticulum membrane that find appropriate protein cargo for transport to the Golgi. He is also trying to identify molecules that help protein-laden vesicles move from the Golgi out of the cell. Schekman, with as much passion for science today as he has had throughout his career, is confident he can persuade Nature to reveal undiscovered routes in her traffic patterns.
Professor, Molecular & Cellular Physiology
Professor (By courtesy), Neurology & Neurological Sciences
Professor (By courtesy), Psychiatry & Behavioral Science
Honors and Awards
Lasker~DeBakey Basic Medical Research Award, Albert and Mary Lasker Foundation (2013)
Elected member, American Academy of Arts and Sciences (2010)
Kavli Prize in Neuroscience, Kavli Foundation (2010)
Elected member, Institute of Medicine (2008)
Elected member, National Academy of Sciences (2002)
Research & Scholarship
Current Research and Scholarly Interests
Human thought and perception, emotions and actions universally depend on signaling between neurons in the brain. This signalling largely happens at synapses, specialized intercellular junctions formed by pre- and postsynaptic neurons. When stimulated, a presynaptic neuron releases chemical messages?called neurotransmitters? that is recognized by a postsynaptic neuron.
For decades, the majority of neuroscientists focused their research on the postsynaptic neuron and its role in learning and memory. But throughout his career, Thomas Sudhof has studied the presynaptic neuron. His collective findings have provided much of our current scientific understanding of presynaptic neuron behavior in neurotransmission and synapse formation. His work also has revealed the role of presynaptic neurons in neuropsychiatric illnesses, such as autism or neurodegenerative disorders.
Born in Germany, Sudhof obtained a medical degree from the University of Gottingen in 1982. He became familiar with neuroscience when he performed research for his doctoral degree at the Max Planck Institute for Biophysical Chemistry. His thesis dealt with the release of hormones from adrenal cells, a model of neurotransmitter release.
To expand his knowledge of biochemistry and molecular biology, Sudhof started to work in 1983 as a postdoctoral fellow at the laboratories of Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center at Dallas. He cloned the gene for the receptor of LDL (the low-density lipoprotein), a particle in the blood that transports cholesterol. Moreover, his work identified the sequences that mediate the regulation of the LDL receptor gene expression by cholesterol.
In 1986, Sudhof started his own laboratory at UT Southwestern. He began his inquiry into the presynaptic neuron. At the time, what scientists mainly knew about the presynaptic neuron was that calcium ions stimulate the release of neurotransmitters from membrane-bound sacs called vesicles into the synapse, in a process that takes less than a millisecond.
But much was unknown: What allowed rapid neurotransmitter release? How did release occur at the specific region of the neuron?the synapse? How did repeated activity change the presynaptic neuron? How did the pre- and postsynaptic neurons come together at the synapse?
Sudhof decided to try to answer these questions. Among the discoveries in his 20 years of research, Sudhof revealed how synaptotagmin proteins sense calcium and mediate neurotransmitter release from presynaptic neurons. He also defined the molecules that organize release in space and time at a synapse, such as RIMs and Munc13's, and identified central components of the presynaptic machinery that mediate the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane, the process that ultimately causes neurotransmitter release, and that is controlled by synaptotagmins.
Sudhof's work also revealed how pre- and postsynaptic proteins form physical connections, permitting neurotransmission. Specifically, he identified proteins on presynaptic neurons, called neurexins, and proteins on the postsynaptic neuron, called neuroligins, that bind to each other at the synapse. There are many types of neurexins and neuroligins. Their variable pairing shapes the wide variability in the types of synapses in the brain. Mutations in these proteins severely impair synapse function in mice, and contribute to the pathogenesis of disease such as autism and schizophrenia in humans.
At present, Sudhof's lab attempts to build on these findings in defining the relationship between specific synaptic proteins and information processing in the brain, with its concordant manifestations in behavior. This large-scale project attempts to provide insight both into the mechanisms undelying synaptic communication, and the processes causing human disease.
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