Heads of Laboratories
Proteins, the primary catalysts of life, are made up of 20 building blocks called amino acids. The lengths of proteins vary and range from about 100 to 10,000 amino acids, strung together in a chain that folds three-dimensionally into distinct shapes as determined by the sequence of the amino acids. Dr. Blobel’s lab uses genetic, biochemical and ultrastructural methods to elucidate protein production, structure and regulation.
To properly function, newly synthesized proteins must be targeted to specific cellular membranes to either pass across or be stitched into the membrane in a way that is characteristic for each membrane protein. Research in Dr. Blobel’s laboratory has established that these processes are specified by short intrinsic regions of the protein chain that function like bar codes. A number of specific components (proteins or RNA-protein complexes), each dedicated to recognize a given bar code, affect the location of the protein within a distinct cellular compartment or mediate the threading of the protein chain into the membrane in a topology that is specified by the bar codes and that is therefore characteristic for each integral membrane protein.
Using principally baker’s yeast and cultured mammalian cells as model systems, Dr. Blobel’s laboratory employs genetic, biochemical and ultrastructural approaches. Among the chief research goals in Dr. Blobel’s laboratory are defining the structure of the nuclear pore complex (NPC) at atomic resolution; elucidating the structural interactions of the basic subunits of chromatin, the nucleosomes, with histone-modifying enzymes and their interacting proteins at atomic resolution; defining the interaction of integral membrane proteins that bridge the outer and inner nuclear membrane with specific heterochromatin regions and the cytoskeleton; and investigating the association of NPC proteins (collectively termed nucleoporins or nups) with the mitotic spindle during cell division.
Dr. Blobel’s laboratory has isolated and characterized most of the transport factors that recognize the bar codes for protein import into the nucleus and identified the first nups. Efforts by several laboratories culminated recently in a complete inventory of nups. Surprisingly, the very large NPC consists of only 30 distinct proteins. In cells of vertebrates, but not in yeast cells, NPCs disassemble during mitosis into subcomplexes that associate in part with the mitotic spindle.
Recently, the Blobel laboratory has begun to study the structure of histone-modifying enzymes at atomic resolution. The goal is to assemble these enzymes with other interacting proteins and with nucleosomes into larger structures and to examine them by x-ray crystallography and cryoelectron microscopy.
Several laboratories have recently described the presence of nups, nuclear transport factors and even lamins in the mitotic spindle. However, the biochemical mechanisms and consequences of these interactions remain largely unexplored. The Blobel laboratory is working to define these interactions.
Lamins, discovered in Dr. Blobel’s laboratory, form the fibrous lamina that is sandwiched between the peripheral chromatin and the inner nuclear envelope membrane. Specific membrane proteins of the inner nuclear membrane were discovered to interact with the lamins and with chromatin. Further work continues to elucidate these interactions at the molecular and structural level.
Dr. Blobel’s research has helped lead to a more detailed understanding of human physiology and pathology. Mutations in the bar code result in protein mistargeting, which in turn causes numerous abnormalities and diseases. Several forms of leukemia are caused by chromosome translocations in which chromosomes are broken at loci coding for nups, yielding fusion proteins containing only a portion of the nup. At least eight rare genetic diseases, termed laminopathies, are based on mutations in the lamin A gene. For reasons yet unknown and dependent on the location of the mutation in the lamin A gene, certain neurons or fat or muscle cells die.
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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