Heads of Laboratories
GŁnter Blobel, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
John D. Rockefeller Jr. Professor
Laboratory of Cell Biology
Among the cell’s diverse transport channels, nuclear pore complexes are by far the largest and most versatile, consisting of approximately 30 distinct proteins known as nucleoporins. Current efforts in the Blobel lab aim to elucidate nuclear pore complex structure at atomic resolution.
Nuclear pore complexes have a mass of over 100 million Daltons, two orders of magnitude larger than any other cellular channel. They are also highly versatile, because transport substrates include both proteins and nucleoproteins. Moreover, transport through the nuclear pore complex is selective and bidirectional. And with approximately 1,000 copies per nucleated cell, nuclear pore complexes are among the most abundant channels in multicellular organisms — humans with approximately 10 12 cells have around 1015 nuclear pore complexes. Not surprisingly, malfunctioning of nuclear pore complexes and nucleo-cytoplasmic transport gives rise to numerous diseases. The term “nuclear pore complex” was introduced in 1958 by Michael Watson, working in the Rockefeller University laboratory of Keith Porter and George Palade.
Because of the eight-fold symmetry of the nuclear pore complex, each of the nucleoporins occurs in multiples of eight copies. The Blobel lab is working to elucidate nuclear pore complex structure at atomic resolution. Toward this goal, nucleoporins (or segments thereof, termed “protomers”) are expressed in bacterial cells, purified, crystallized and analyzed by x-ray crystallography. Protomers are also assembled and investigated by cryo-electron microscopy. Structural studies are augmented by biophysical and cell biological approaches. Similar approaches are employed to analyze interactions between transport factors and nucleoporins.
The crystallographic and biophysical data of the Blobel laboratory on protomers of three “channel” nucleoporins (Nup54, Nup58 and Nup62) have provided new insights into the mechanism of opening and closing of the central transport channel of the nuclear pore complex. A key discovery was that a given segment, each of nucleoporin Nup54 and Nup58, form oligomeric assemblies of different conformations. Twenty-four conformers (homo-tetramers) assemble into three small, eight-membered rings (closed channel); eight other conformers (hetero-dodecamers) assemble into a single large ring (open channel). The transition between three small rings and a single large ring (the “ring cycle”) changes the diameter of the central transport channel by as much as 40 nanometers, enough to allow for the passage of a large ribosomal subunit or a virus.
This ring cycle is regulated by transport factor occupancy of a non-structured region of Nup58, whereby cargo-occupied transport factors serve both as ligands and the transport substrate. Ligand binding provides the energy for stabilizing “dilated” conformers (hetero-dodecamers); below a threshold of occupied ligand binding sites, “constricted” conformers (homo-tetramers) prevail and keep the channel in a closed form.
A native of Germany, Dr. Blobel received his M.D. from the University of Tübingen in 1960 and his Ph.D. in 1967 from the University of Wisconsin, Madison, where he worked with Van R. Potter in the McArdle Laboratory for Cancer Research. He did postdoctoral work at The Rockefeller University in the laboratory of George E. Palade and has been at the university since then. He was named the John D. Rockefeller Jr. Professor in 1992 and became an investigator at the Howard Hughes Medical Institute in 1986.
Dr. Blobel was the 1999 recipient of the Nobel Prize in Physiology or Medicine for his discovery that proteins have intrinsic signals that govern their transport and localization in the cell. He also received the King Faisal International Prize in 1996, the Albert Lasker Award for Basic Medical Research in 1993, the Louisa Gross Horwitz Prize in 1989 and the Gairdner Foundation International Award in 1982. He is a member of the National Academy of Sciences, the American Philosophical Society, the Pontifical Academy of Sciences and the German Order of Merit. He was awarded an honorary degree from The Rockefeller University in 2013.
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