Faculty and Research
Faculty by Name
Randy Schekman
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Randy Schekman
Howard Hughes Investigator and Professor of Cell and Developmental Biology*
*And Affiliate, Division of Biochemistry and Molecular Biology
Research Interests
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Our research is on the mechanism and control of intracellular protein transport in Saccharomyces cerevisiae and mammalian cells. In particular we are studying the secretory process and its role in the assembly of cellular organelles. Enzymology, genetics, and electron microscopy are employed in this investigation.
Current Projects
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Protein translocation into the lumen of the endoplasmic reticulum represents the initial step in assembly of the eukaryotic cell surface. Sec61p forms the channel in the ER membrane through which secretory polypeptides pass from the cytoplasm into the lumen. Misfolded secretory proteins are removed from the ER by reverse translocation, though the channel responsible for this process remains to be clearly identified.
Subsequent stages in the secretory pathway involve protein sorting and transport from the endoplasmic reticulum and the Golgi complex and from there to the cell surface. Vesicle budding from the ER requires four proteins: A small GTP-binding protein called Sar1p, a complex (Sec23/Sec24) that is required to stimulate GTP hydrolysis by Sar1p, an integral membrane protein (Sec12p) that facilitates nucleotide exchange by Sar1p, and another complex (Sec13/Sec31) that forms an outer scaffold to shape a bud and cleave the vesicle from the ER membrane. These proteins comprise a novel coat protein complex, COPII. Several of the COPII genes are duplicated in mammals: Two copies of SAR1, two of SEC23, four of SEC24 and two of SEC31. SEC23A is defective in patients with a rare craniofacial disease in which a point of contact between the inner layer of the coat (Sar1-Sec23/24) is mutated to a residue (F382L) that reduces the affinity for Sec31 of the scaffold layer on the coat (Sec13/31). As a result ER buds are elongated to produce tubules that fail to resolve into vesicles.
A model for the binding of coat proteins and capture of membrane molecules in COPII vesicles.
Secretory and membrane proteins must be sorted and packaged into distinct transport carriers at the trans Golgi membrane, yet the mechanism of cargo protein discrimination and vesicle budding at this station remain unclear. Although some proteins use clathrin to traverse the endosome en route to the plasma membrane, others do not, and, until now, the general view has been that the direct path out of the trans-Golgi network (TGN) may involve tubular carriers formed without the intervention of coat proteins. To examine this limb of the secretory pathway in yeast, we have focused on two membrane proteins: A biosynthetic enzyme, chitin synthase III (Chs3p) and a mating cell fusion protein, Fus1p, which travel from the TGN/endosome to the plasma membrane in yeast.
Chs3p and Fus1p are conveyed from the TGN by a novel coat protein complex called exomer. Exomer complex binds membranes in the presence of a GTP-activated form of Arf1p, a small GTPase implicated in other coat assembly events. Unlike other coats, however, exomer is responsible for the traffic of a nonessential set of cell surface proteins. Additional coat complexes, perhaps structurally related to exomer, may provide the sorting and vesicle formation activity necessary for the traffic of essential plasma membrane proteins in mammalian cells.
Mammalian cells transport a more complex set of proteins to the cell surface and to intracellular compartments. We are examining the traffic of a membrane protein, amyloid precursor protein (APP), and an enzyme that proteolytically cleaves APP, gamma-secretase, as they come into contact in an endosomal membrane where APP is broken into amyloid peptide fragments. Amyloid peptide formation in the endosome is directly related to the development of Alzheimer's Disease which is accelerated in patients who have familial forms of the disease that are caused by mutations in the genes for APP or the catalytic subunit of gamma-secretase.
Selected Publications
- Please visit the Schekman lab website for a current list of publications.
Last Updated 2009-03-16