Heads of Laboratories
Investigator, Howard Hughes Medical Institute
John D. Rockefeller Jr. Professor
Laboratory of Cell Biology
Using X-ray crystallography, cryo-electron microscopy, biophysical, and cell-biological approaches, the Blobel lab focuses primarily on the structure and dynamics of the nuclear pore complex, a selective transport channel into and out of the nucleus. Dr. Blobel is also interested in the remodeling of messenger ribonucleoprotein (mRNP) prior, during, and after its transport across nuclear membrane, in the cytoplasmic transport of mRNA, and in the biosynthesis and uptake of cholesterol.
Research in the Blobel laboratory focuses on four areas:
1. Nuclear pore complex structure and dynamics. In 1986, the Blobel laboratory discovered the first proteins that make up the nuclear pore complex, and named them nucleoporins. It was subsequently shown that the nuclear pore complex consists of multiple copies of about 30 distinct nucleoporins. The lab also isolated and characterized the first transport factors mediating nucleo-cytoplasmic transport and identified their binding sites on nucleoporins. In 2004, Dr. Blobel’s lab began crystallographic analyses of interacting regions of nucleoporins with the aim of piecing together an atomic structure for the nuclear pore complex.
Early on, they discovered that identical segments of nucleoporins crystallized in distinct conformers, revealing the dynamic nature of their interactomes. Especially striking examples were found for two nucleoporins, Nup58 and Nup54. Crystal snapshots of cognate segments showed several distinct conformers and led to the proposal of a “ring cycle” for channel structure and dynamics. Based on the conformers’ dimensions and axes of symmetry and on the known eight-fold rotational symmetry of the nuclear pore complex, the ring cycle model proposed that eight hetero-dodecamers form a single large mid-plane ring of approximately 40 nanometers in diameter, whereas eight homo-tetramers form three smaller rings of 10 to 20 nanometers in diameter. In this model, the large mid-plane ring represents the dilated form, whereas the smaller rings represent the constricted form of the central channel. Calorimetric analyses indicated that occupation of transport factor binding sites present in an extended Nup58 segment cause allosteric stabilization of the dilated conformer at the expense of the constricted conformer.
2. Messenger ribonucleoprotein (mRNP) remodeling. Stepwise removal of mRNA-bound proteins on the cytoplasmic side of the nuclear pore complex is mediated by a nucleoporin-anchored ATPase that removes mRNA-bound proteins, one per each ATPase cycle, and thereby achieves transport of mRNA to the cytoplasm in a molecular ratchet-type mechanism. A specific viral protein interferes with this mechanism and thereby inhibits nuclear export of host mRNAs.
3. Cytoplasmic mRNA transport. Certain mRNAs are marked by “zip-code” element(s) and are actively transported to specific regions in the cytoplasm. Crystal structures of interactomes between myosin and an adaptor protein provided clues about the assembly of such a cytoplasmic mRNA transport complex.
4. Membrane proteins in cholesterol biosynthesis and cholesterol uptake. In 1988, the Blobel laboratory identified a lamin B receptor, a multifunctional integral membrane protein in the inner nuclear membrane. The C-terminal half of this receptor is highly homologous to sterol reductases, and the cDNA of the human lamin B receptor complements reductase gene deletion in yeast. A crystal structure of an Archaea homolog showed 10 transmembrane segments and yielded insights into lamin B receptor and sterol reductase function and diseases caused by human mutations.
University of Tübingen
Ph.D. in oncology, 1967
University of Wisconsin, Madison
The Rockefeller University, 1967–1969
Assistant Professor, 1969–1973
Associate Professor, 1973–1976
The Rockefeller University
Howard Hughes Medical Institute
U.S. Steel Award, 1978
Canada Gairdner International Award, 1982
Warburg Medal, German Biochemical Society, 1983
Richard Lounsbery Award, 1983
V.D. Mattia Award, 1986
Wilson Medal, American Society for Cell Biology, 1986
Louisa Gross Horwitz Prize, 1989
Albert Lasker Basic Medical Research Award, 1993
King Faisal International Prize, 1996
New York City Mayor’s Award for Excellence in Science and Technology, 1997
Massry Prize, 1999
Nobel Prize in Physiology or Medicine, 1999
National Academy of Sciences
American Philosophical Society
Pontifical Academy of Sciences
German Order of Merit
Koh, J. and Blobel, G. Allosteric regulation in gating the central channel of the nuclear pore complex. Cell 161, 1361–1373 (2015).
Singh, N. et al. Hooking She3p onto She2p for myosin-mediated cytoplasmic mRNA transport. Proc. Natl. Acad. Sci. U.S.A. 112, 142–147 (2015).
Li, X. et al. Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum. Nature 517, 104–107 (2015).
Quan, B. et al. Vesiculoviral matrix (M) protein occupies nucleic acid binding site at nucleoporin pair (Rae1 • Nup98). Proc. Natl. Acad. Sci. U.S.A. 111, 9127–9132 (2014).