SST2/YLR452C Summary Help

Standard Name SST2 1, 2
Systematic Name YLR452C
Feature Type ORF, Verified
Description GTPase-activating protein for Gpa1p; regulates desensitization to alpha factor pheromone; also required to prevent receptor-independent signaling of the mating pathway; member of the RGS (regulator of G-protein signaling) family (3, 4, 5 and see Summary Paragraph)
Name Description SuperSensiTive 1
Chromosomal Location
ChrXII:1041366 to 1039270 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Gbrowse
Genetic position: 344 cM
Gene Ontology Annotations All SST2 GO evidence and references
  View Computational GO annotations for SST2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 14 genes
Resources
Classical genetics
null
Large-scale survey
null
Resources
231 total interaction(s) for 161 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 12
  • Affinity Capture-RNA: 3
  • Affinity Capture-Western: 4
  • Biochemical Activity: 3
  • Co-fractionation: 1
  • Protein-RNA: 1
  • Reconstituted Complex: 1
  • Two-hybrid: 19

Genetic Interactions
  • Dosage Rescue: 4
  • Negative Genetic: 139
  • Phenotypic Enhancement: 4
  • Phenotypic Suppression: 6
  • Positive Genetic: 14
  • Synthetic Growth Defect: 7
  • Synthetic Lethality: 7
  • Synthetic Rescue: 6

Resources
Expression Summary
histogram
Resources
Length (a.a.) 698
Molecular Weight (Da) 79,716
Isoelectric Point (pI) 8.82
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXII:1041366 to 1039270 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
SGD ORF map
Genetic position: 344 cM
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..2097 1041366..1039270 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000004444
SUMMARY PARAGRAPH for SST2

SST2 encodes a GTPase activating protein that stimulates GTP hydrolysis on the G protein alpha subunit Gpa1p (3, 6). Stimulation of GTP hydrolysis by Sst2p leads to downregulation of the pheromone response pathway and recovery of pheromone-induced cells; thus, Sst2p negatively regulates pheromone response (1).

Haploid yeast cells exist as one of two mating types, MATa or MATalpha. Mating of haploid cells to form diploids is initiated when the peptide pheromones produced by either cell type (a factor or alpha factor) bind to seven-transmembrane receptor proteins on cells of the opposite type: Ste2p (MATa cells) or Ste3p (MATalpha cells) (7, 8). Pheromone binding leads to activation of the heterotrimeric G-protein composed of alpha subunit Gpa1p, beta subunit Ste4p, and gamma subunit Ste18p (9, 10, 11). Activation is mediated by exchange of GDP for GTP on the alpha subunit, causing the heterotrimer to dissociate. The resulting Ste4p-Ste18p dimer mediates signal transduction through binding to both the scaffolding protein Ste5p and the PAK kinase Ste20p, causing activation of a MAP kinase cascade (Ste11p, Ste7p, and Fus3p; 12, 13). The Ste4p-Ste18p dimer also interacts with a complex of Far1p and Cdc24p; in total, these interactions induce expression of genes involved in mating, polarization of cell growth, and ultimately cell and nuclear fusion (reviewed in 14). One mechanism by which pheromone response is negatively regulated is by hydrolysis of Gpa1p-bound GTP, a process stimulated by interaction with between Gpa1p and Sst2p (3). Hydrolysis of GTP converts Gpa1p back to the GDP-bound form, which can then sequester the active Ste4p-Ste18p complex into the inactive heterotrimer, thereby dampening the pheromone-induced signal (reviewed in 14 and 15).

Null sst2 mutations cause supersensitivity to both the alpha factor and a factor pheromones, and mutant cells do not recover from pheromone-induced growth arrest (1, 16, 17). Sst2p is also required to prevent activation of the pheromone response pathway in the absence of receptor (4). Expression of Sst2p is haploid specific and is induced by pheromone (17, 6); moreover, Sst2p is phosphorylated at Ser-539 by the mitogen-activated protein (MAP) kinase Fus3p upon pheromone treatment. (18, 19). The presence of pheromone also promotes ubiquitination and subsequent degradation of Sst2p (20).

Sst2p is a member of the RGS (Regulators of G protein Signaling) family (6). RGS proteins act by binding and stabilizing the three regions of G alpha subunits that undergo conformational change upon GTP hydrolysis; this stabilization of the transition state leads to an increase in the reaction rate (21, 22). Indeed, purified Sst2p stimulates GTP hydrolysis (3), and Sst2p binds with highest affinity to the transition state of hydrolysis (mimicked using Gpa1p bound to a complex of GDP and aluminum tetrafluoride; GDP-AlF4), and with much lower affinity to the inactive (GDP-bound) and active (GTPgammaS-bound) conformations (3).

RGS proteins share a conserved region called the RGS domain (residues 420-698 of Sst2p), which is comprised of 3 highly conserved GH (GAIP or Gos8 Homology subdomains); in Sst2p these GH elements are dispersed within the C-terminus. Some RGS proteins contain N-terminal regions that may function to enhance the efficacy of the GAP activity (reviewed in 15 and 23). The Sst2p N-terminal region contains a conanical DEP domain (residues 279-358) and a DEP-like segment (residues 50-135), which are required for Sst2p function in cis to the C-terminal RGS domain and which mediate interaction with the C-terminal tail of the Ste2p receptor (24). In addition, Sst2p has been shown to interact with Mpt5p, a protein that also interacts with Fus3p and has an apparent role in recovery from pheromone arrest (25), through the N-terminal MPI (Mpt5p-interacting) domain (residues 1-401) of Sst2p (26).

S. cerevisiae encodes at least four RGS proteins: Sst2p, Rgs2p, which accelerates GTP hydrolysis on Gpa2p (27), and the less well characterized proteins Rax1p and Mdm1p (reviewed in 28). The mammalian genome encodes approximately 40 RGS proteins (reviewed in 28). Polymorphisms in human RGS4, and alterations in its expression, have been associated with schizophrenia (29). Studies in mice indicating that mutations in RGS2 confer a hypertensive phenotype suggest a link between this gene and hypertension in humans (30).

Last updated: 2007-06-21 Contact SGD

References cited on this page View Complete Literature Guide for SST2
1) Chan RK and Otte CA  (1982) Isolation and genetic analysis of Saccharomyces cerevisiae mutants supersensitive to G1 arrest by a factor and alpha factor pheromones. Mol Cell Biol 2(1):11-20
2) Chan, R.K.  (1985) Personal Communication, Mortimer Map Edition 9
3) Apanovitch DM, et al.  (1998) Sst2 is a GTPase-activating protein for Gpa1: purification and characterization of a cognate RGS-Galpha protein pair in yeast. Biochemistry 37(14):4815-22
4) Siekhaus DE and Drubin DG  (2003) Spontaneous receptor-independent heterotrimeric G-protein signalling in an RGS mutant. Nat Cell Biol 5(3):231-5
5) Siderovski DP, et al.  (1996) A new family of regulators of G-protein-coupled receptors? Curr Biol 6(2):211-2
6) Dohlman HG, et al.  (1996) Sst2, a negative regulator of pheromone signaling in the yeast Saccharomyces cerevisiae: expression, localization, and genetic interaction and physical association with Gpa1 (the G-protein alpha subunit). Mol Cell Biol 16(9):5194-209
7) Burkholder AC and Hartwell LH  (1985) The yeast alpha-factor receptor: structural properties deduced from the sequence of the STE2 gene. Nucleic Acids Res 13(23):8463-75
8) Hagen DC, et al.  (1986) Evidence the yeast STE3 gene encodes a receptor for the peptide pheromone a factor: gene sequence and implications for the structure of the presumed receptor. Proc Natl Acad Sci U S A 83(5):1418-22
9) Whiteway M, et al.  (1989) The STE4 and STE18 genes of yeast encode potential beta and gamma subunits of the mating factor receptor-coupled G protein. Cell 56(3):467-77
10) Dietzel C and Kurjan J  (1987) The yeast SCG1 gene: a G alpha-like protein implicated in the a- and alpha-factor response pathway. Cell 50(7):1001-10
11) Miyajima I, et al.  (1987) GPA1, a haploid-specific essential gene, encodes a yeast homolog of mammalian G protein which may be involved in mating factor signal transduction. Cell 50(7):1011-9
12) Leeuw T, et al.  (1998) Interaction of a G-protein beta-subunit with a conserved sequence in Ste20/PAK family protein kinases. Nature 391(6663):191-5
13) Dowell SJ, et al.  (1998) Mapping of a yeast G protein betagamma signaling interaction. Genetics 150(4):1407-17
14) Bardwell L  (2005) A walk-through of the yeast mating pheromone response pathway. Peptides 26(2):339-50
15) Dohlman HG and Thorner J  (1997) RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem 272(7):3871-4
16) Chan RK and Otte CA  (1982) Physiological characterization of Saccharomyces cerevisiae mutants supersensitive to G1 arrest by a factor and alpha factor pheromones. Mol Cell Biol 2(1):21-9
17) Dietzel C and Kurjan J  (1987) Pheromonal regulation and sequence of the Saccharomyces cerevisiae SST2 gene: a model for desensitization to pheromone. Mol Cell Biol 7(12):4169-77
18) Garrison TR, et al.  (1999) Feedback phosphorylation of an RGS protein by MAP kinase in yeast. J Biol Chem 274(51):36387-91
19) Parnell SC, et al.  (2005) Phosphorylation of the RGS protein Sst2 by the MAP kinase Fus3 and use of Sst2 as a model to analyze determinants of substrate sequence specificity. Biochemistry 44(22):8159-66
20) Hao N, et al.  (2003) Regulators of G protein signaling and transient activation of signaling: experimental and computational analysis reveals negative and positive feedback controls on G protein activity. J Biol Chem 278(47):46506-15
21) Tesmer JJ, et al.  (1997) Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell 89(2):251-61
22) Berman DM, et al.  (1996) The GTPase-activating protein RGS4 stabilizes the transition state for nucleotide hydrolysis. J Biol Chem 271(44):27209-12
23) Burchett SA  (2000) Regulators of G protein signaling: a bestiary of modular protein binding domains. J Neurochem 75(4):1335-51
24) Ballon DR, et al.  (2006) DEP-domain-mediated regulation of GPCR signaling responses. Cell 126(6):1079-93
25) Chen T and Kurjan J  (1997) Saccharomyces cerevisiae Mpt5p interacts with Sst2p and plays roles in pheromone sensitivity and recovery from pheromone arrest. Mol Cell Biol 17(6):3429-39
26) Xu BE, et al.  (2001) The N terminus of Saccharomyces cerevisiae Sst2p plays an RGS-domain-independent, Mpt5p-dependent role in recovery from pheromone arrest. Genetics 159(4):1559-71
27) Versele M, et al.  (1999) A novel regulator of G protein signalling in yeast, Rgs2, downregulates glucose-activation of the cAMP pathway through direct inhibition of Gpa2. EMBO J 18(20):5577-91
28) Chasse SA, et al.  (2006) Genome-scale analysis reveals Sst2 as the principal regulator of mating pheromone signaling in the yeast Saccharomyces cerevisiae. Eukaryot Cell 5(2):330-46
29) Gu Z, et al.  (2007) RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. Mol Pharmacol 71(4):1030-9
30) Heximer SP, et al.  (2003) Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest 111(4):445-52