Biography

Randy Schekman is a Professor in the Department of Molecular and Cell Biology, University of California, Berkeley, and an Investigator of the Howard Hughes Medical Institute. He studied the enzymology of DNA replication as a graduate student with Arthur Kornberg at Stanford University. His current interest in cellular membranes developed during a postdoctoral period with S. J. Singer at the University of California, San Diego. At Berkeley, he developed a genetic and biochemical approach to the study of eukaryotic membrane traffic. Among his awards are the Eli Lilly Award in microbiology and immunology, the Lewis S. Rosenstiel Award in basic biomedical science, the Gairdner International Award, the Amgen Award of the Protein Society, the Albert Lasker Award in Basic Medical Research and the Louisa Gross Horwitz Prize of Columbia University. He has been awarded honorary doctorate degrees from the University of Geneva and the University of Regensburg. He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. In 1999, he was elected President of the American Society for Cell Biology and was appointed Editor of the Annual Review of Cell and Developmental Biology. In 2002, he was elected Chair of the Biochemistry Section of the National Academy of Sciences and was selected as Scientific Director of the Jane Coffin Childs Memorial Fund for Biomedical Research. In 2005, he was elected Chair of the Biology Class of the NAS and this year he has been appointed Editor-in Chief of the Proceedings of the NAS. At UC Berkeley, Schekman has assumed a number of leadership positions in Departmental and campus affairs. In addition to serving a five-year term as Biochemistry Division Head, Schekman served as Chair of the Department of Molecular and Cell Biology. Currently, he serves as Chair of the Chancellor’s Advisory Council on Biology, a virtual College of Biology that represents all 250 life sciences faculty distributed within the College of Letters and Science, School of Public Health, School of Optometry, School of Engineering, College of Chemistry, and College of Natural Resources. In 2004, Schekman organized a campus-wide stem cell biology center to capitalize on California’s investment in the application of human embryonic stem cells to regenerative medicine.
 

Randy Schekman , Ph.D.

Howard Hughes Investigator and Professor of Cell & Developmental Biology
University of California, Berkeley

mcb.berkeley.edu/faculty/CDB/schekmanr.html
mcb.berkeley.edu/labs/schekman/

Morphogenesis of a Transport Vesicle: Mechanism and Disease Connections

Abstract:
Genetics, biochemistry and morphology have been used to understand the mechanism of protein secretion in eukaryotic cells. Membrane and secretory proteins are sorted in the secretory pathway by cytoplasmic coat proteins that assemble on the surface of a donor membrane, bud transport vesicles, and convey cargo proteins to a target membrane. The COPII coat is responsible for all anterograde traffic of cargo from the endoplasmic reticulum to the Golgi complex. COPII assembly is initiated by the recruitment of the GTP-binding protein, Sar1, to the ER membrane through a transient interaction with a guanine nucleotide exchange factor, Sec12, located on the ER. Sar1-GTP extends an amphipathic N-terminal helix that embeds in the ER bilayer and deforms the membrane into a pleiomorphic tubular carrier. Tethered Sar1 recruits Sec23/24p, which binds potential cargo proteins but not resident ER membrane proteins. Cargo-coat complexes are then clustered by Sec13/31p, which acts as a scaffold to concentrate cargo molecules. The N-terminal helix of Sar1p completes the fission process separating cargo-enriched vesicles from resident proteins that remain behind in the ER.

A rare craniofacial disease, CLSD, has been linked to a conservative substitution in one of two paralogs of the human SEC23 gene. Fibroblasts cultured from CLSD patients display dramatic rough ER tubule distention and a proliferation of smooth tubules that project from the ER exit site. The smooth tubules resemble those formed on synthetic liposomes incubated with Sar1-GTP. A COPII vesicle budding reaction reconstituted from digitonin-permeabilized cultured cells displays a defect in the presence of CLSD mutant recombinant Sec23/24p. Surprisingly, this defect depends on the use of one of the two human Sar1 paralogs, Sar1b, in the budding reaction. The CLSD mutation interferes with recruitment of the Sec13/31p scaffold, thus the elongated smooth tubules that form from the ER exit face in fibroblasts cultured from a CLSD patient probably reflect a failure in the vesicle fission process.