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The Ste5p scaffold

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA

View larger version (33K): [in a new window]   Fig. 1. Multiple MAP kinase (MAPK) cascades using shared components regulate growth and differentiation in S. cerevisiae. Mating, invasive growth, pseudohyphal development, high-osmolarity/glycerol response and maintenance of cell wall integrity are each regulated by structurally similar but functionally distinct MAPK cascades that are activated by different upstream signals but have in common at least three kinds of kinases: a MAPKKK, a MAPKK (or MEK) and a MAPK. Yellow highlighting indicates the kinases that are shared by the different pathways. Note that for simplicity Ste50p is not shown in this figure (but see Fig. 2), although it associates with Ste11p and is required for optimal signaling through all of the pathways shown. Details can be found elsewhere (Gustin et al., 1998; Elion, 2000; Pan et al., 2000).

View larger version (44K): [in a new window]   Fig. 2. Cartoon of Ste5p, Pbs2p and Far1p scaffolds. Ste5p is required for activation of the mating MAPK cascade in response to mating pheromone and does not have an intrinsic kinase activity, whereas Pbs2p encodes the MAPKK of the high osmolarity/glycerol pathway that is activated by increased osmolarity. Far1p is required for oriented polarized growth in response to mating pheromone. Pbs2p and Far1p are postulated to be analogs of Ste5p on the basis of their ability to associate with multiple components of an individual signal transduction pathway (Posas and Saito, 1997; Butty et al., 1998; Nern and Arkowitz, 1998; Nern and Arkowitz, 1999; Rait et al., 2000), but it is not known whether they simultaneously bind to associated signaling components. Similarities between Ste5p, Pbs2p and Far1p include the ability to associate with an uppermost component of a pathway that is membrane associated and senses the external signal, as well as to downstream components that regulate the activity of effectors within a pathway. In addition, all three scaffolds link signaling components that also associate with a Rho-type G protein (Cdc42p). Ste5p and Far1p share two domains of homology (Leberer et al., 1992), one of which overlaps with the RING-H2 domain that is thought to associate with the Gß subunit Ste4p of the same heterotrimeric G protein. It is not known whether the RING-H2 domains have a function in ubiquitin-mediated proteolysis (Borden, 2001).

View larger version (34K): [in a new window]   Fig. 3. Ste5p conformational models. Two models for how the binding of Gß to Ste5p induces a conformational change in either (A) a folded dimer or (B) an anti-parallel dimer that is formed through interactions between the N- and C-terminal halves of Ste5p. The binding of the Gß dimer (Ste4p and Ste18p) is postulated to align the associated kinases so as to permit serial phosphoryation. The models are adapted from (Sette et al., 2000); see text for details. Note that serial phosphorylations would occur in cis in model A and in trans in model B.

View larger version (30K): [in a new window]   Fig. 4. Ste5p oligomerization/recruitment model. An alternative model, in which a Ste5p dimer forms higher-order oligomers by binding to Gß. In this scenario, a Ste5p dimer can exist with a protected RING-H2 domain as a folded dimer of parallel strands or dimer of anti-parallel strands (A) or as an open dimer of parallel strands in which the RING-H2 domain is accessible to homo-dimerize and bind Gß (B). Higher-order oligomers can form through N- to C-terminal interactions, the binding of Gß driving the formation of higher-order oligomers at the plasma membrane by interfering with intramolecular interactions. Two types of higher-order oligomer are shown: tandem head-to-tail oligomers and stacked anti-parallel oligomers. The higher-order oligomers could conceivably promote serial phosphorylation in trans.

View larger version (46K): [in a new window]   Fig. 5. Far1p-Ste5p interactions. Summary of potential related functional and physical interactions for both proteins, showing the fact that Far1p, Ste5p and Cdc24p all shuttle through the nucleus with the nuclear pool able to translocate to the cell periphery. Here it is pointed out that Far1p is a Fus3p substrate and that Ste5p could potentially target Cdc24p through its own interactions with Bem1p. See text for details.