Interactions between Rabs, tethers, SNAREs and their regulators in exocytosis.
Sec2p is the exchange factor that activates Sec4p, the Rab GTPase controlling the final stage of the yeast exocytic pathway. Sec2p is recruited to secretory vesicles by Ypt32-GTP, a Rab controlling exit from the Golgi. Sec15p, a subunit of the octameric exocyst tethering complex and an effector of Sec4p, binds to Sec2p on secretory vesicles, displacing Ypt32p. Sec2p mutants defective in the region 450-508 amino acids bind to Sec15p more tightly. In these mutants, Sec2p accumulates in the cytosol in a complex with the exocyst and is not recruited to vesicles by Ypt32p. Thus the region 450-508 amino acids negatively regulates the association of Sec2p with the exocyst, allowing it to recycle on to new vesicles. The structures of one nearly full-length exocyst subunit and three partial subunits have been determined and, despite very low sequence identity, all form rod-like structures built of helical bundles stacked end to end. These rods may bind to each other along their sides to form the assembled complex. While Sec15p binds Sec4-GTP on the vesicle, other subunits bind Rho GTPases on the plasma membrane, thus tethering vesicles to exocytic sites. Sec4-GTP also binds Sro7p, a yeast homologue of the Drosophila lgl (lethal giant larvae) tumour suppressor. Sro7 also binds to Sec9p, a SNAP25 (25 kDa synaptosome-associated protein)-like t-SNARE [target-membrane-associated SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor)], and can form a Sec4p-Sro7p-Sec9p ternary complex. Overexpression of Sec4p, Sro7p or Sec1p (another SNARE regulator) can bypass deletions of three different exocyst subunits. Thus promoting SNARE function can compensate for tethering defects.
Novick
P
P
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. peter.novick@yale.edu
Medkova
M
M
Dong
G
G
Hutagalung
A
A
Reinisch
K
K
Grosshans
B
B
D002462:Cell Membrane / Q000502:physiology; D005089:Exocytosis / Q000502:physiology*; D006706:Homeostasis; D008954:Models, Biological; D050600:SNARE Proteins / Q000378:metabolism*; D022142:Secretory Vesicles / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
D050600:SNARE Proteins; D020691:rab GTP-Binding Proteins