SCS2/YER120W Summary Help

Standard Name SCS2 1
Systematic Name YER120W
Feature Type ORF, Verified
Description Integral ER membrane protein, regulates phospholipid metabolism; one of 6 proteins (Ist2p, Scs2p, Scs22p, Tcb1p, Tcb2p, Tcb3p) that connect ER to the plasma membrane (PM) and regulate PI4P levels by controlling access of Sac1p phosphatase to its substrate PI4P in the PM; interacts with FFAT motif of Opi1p; involved in telomeric silencing; null shows inositol auxotrophy above 34 deg C; VAP homolog; SCS2 has a paralog, SCS22, that arose from the whole genome duplication (2, 3, 4, 5, 6, 7 and see Summary Paragraph)
Name Description Suppressor of Choline Sensitivity 8
Chromosomal Location
ChrV:401135 to 401869 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All SCS2 GO evidence and references
  View Computational GO annotations for SCS2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 5 genes
Resources
Classical genetics
null
overexpression
reduction of function
Large-scale survey
null
overexpression
Resources
313 total interaction(s) for 184 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 69
  • Affinity Capture-RNA: 2
  • Affinity Capture-Western: 5
  • Co-purification: 1
  • PCA: 5
  • Reconstituted Complex: 1

Genetic Interactions
  • Dosage Lethality: 2
  • Dosage Rescue: 12
  • Negative Genetic: 149
  • Phenotypic Enhancement: 4
  • Phenotypic Suppression: 3
  • Positive Genetic: 32
  • Synthetic Growth Defect: 18
  • Synthetic Lethality: 5
  • Synthetic Rescue: 5

Resources
Expression Summary
histogram
Resources
Length (a.a.) 244
Molecular Weight (Da) 26,925
Isoelectric Point (pI) 4.67
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrV:401135 to 401869 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..735 401135..401869 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 SGDIDS000000922
SUMMARY PARAGRAPH for SCS2

SCS2 encodes a type II integral membrane protein and VAP (VAMP/synaptobrevin-associated protein) family member that localizes to both the endoplasmic reticulum (ER) and nuclear membranes (2, 9) where it regulates intracellular lipid traffic and phospholipid biosynthesis (9). A region of Scs2p that is conserved in VAP family members constitutes the binding site for a short membrane-targeting determinant called the FFAT motif (two phenylalanines (FF) in an Acidic Tract). The FFAT motif is located in several sterol-binding proteins involved in intracellular sterol transport (Swh1p, Osh2p and Osh3p) and in a transcriptional corepressor of phospholipid biosynthetic genes (Opi1p) (5, 9). Interactions between Scs2p and the sterol-binding proteins regulate intracellular lipid transport by targeting these proteins to the ER membrane, the site of synthesis for most lipids (9). Under conditions where inositol is limiting and the unfolded protein response (UPR) activated, direct interactions between Scs2p and Opi1p sequester this transcriptional regulator at the ER/nuclear membrane where it can then bind to phosphatidic acid (PA) (9, 10, 11). Upon the addition of inositol, the lipid precursor phosphatidic acid (PA) and cytidyldiphosphate diacylglycerol (CDP-DAG) are converted into phosphatidylinositol (PI), resulting in the consumption of PA, and the release of Opi1p from the membrane followed by its nuclear translocation (reviewed in 12). Thus by regulating the intracellular location of this lipid-sensing transcriptional regulator, Scs2p regulates the negative feedback loop that controls expression of inositol biosynthetic genes. Scs2p also directly regulates the intranuclear localization of the gene encoding inositol 1-phosphate synthase (INO1), the rate-limiting enzyme in inositol biosynthesis (10).

SCS2 was originally identified as a suppressor of the inositol auxotrophy associated with a dominant choline sensitive mutant (8) and with hac1 mutants, both of which are also defective for expression of INO1 (1). scs2 deletion mutants have reduced levels of phosphatidylinositol, increased levels of phophatidylcholine and a leaky inositol auxotrophy when cultured at elevated temperatures (2, 4). The leaky inositol auxotrophy is suppressed by overexpression of INO1 or INO2, or by deletion of genes in the CDP-choline pathway (CKI1, PCT1, and CPT1), a pathway that is upregulated in scs2 deletion mutants (2, 4). Deletion of SCS22, an SCS2-like gene, does not result in inositol auxotrophy but does contribute to the regulation of phospholipid metabolism, as the phenotype associated with the double mutant is more severe than that of an scs2 single mutant (5). SCS2 has also been identified as a multicopy suppressor of strains with telomere silencing defects (3, 13), while deletion of SCS2 results in a loss of telomeric silencing (3).

SCS2 has sequence similarity with members of the VAP protein family including the founding member, VAP-33, an Aplysia gene required for neurotransmitter release (reviewed in 14). Three human VAP family members VAP-A (OMIM), VAP-B (OMIM) and VAP-C (OMIM) (a VAP-B splicing variant) (15) are also involved in recruiting FFAT-motif containing lipid-binding proteins to the ER (16, 5). Human VAP family members have also been implicated in both vesicular trafficking and organization of microtubule networks (references found within 17). The human VAP-A gene can partially complement the function of yeast VAPs by rescuing the inositol auxotrophy of an scs2 scs22 double mutant under less stringent conditions, and this rescue is dependent upon the integrity of the FFAT-binding region of VAP-A (5). Mutations in the human VAP-B gene cause atypical amyotrophic lateral sclerosis (ALS) type 8 (a neurodegenerative disease also known as Lou Gehrig's disease; OMIM), and late-onset spinal muscular atrophy (SMA) (OMIM) (18).

Last updated: 2007-06-01 Contact SGD

References cited on this page View Complete Literature Guide for SCS2
1) Nikawa J, et al.  (1995) Cloning and sequence of the SCS2 gene, which can suppress the defect of INO1 expression in an inositol auxotrophic mutant of Saccharomyces cerevisiae. J Biochem (Tokyo) 118(1):39-45
2) Kagiwada S, et al.  (1998) The Saccharomyces cerevisiae SCS2 gene product, a homolog of a synaptobrevin-associated protein, is an integral membrane protein of the endoplasmic reticulum and is required for inositol metabolism. J Bacteriol 180(7):1700-8
3) Craven RJ and Petes TD  (2001) The Saccharomyces cerevisiae suppressor of choline sensitivity (SCS2) gene is a multicopy Suppressor of mec1 telomeric silencing defects. Genetics 158(1):145-54
4) Kagiwada S and Zen R  (2003) Role of the yeast VAP homolog, Scs2p, in INO1 expression and phospholipid metabolism. J Biochem (Tokyo) 133(4):515-22
5) Loewen CJ and Levine TP  (2005) A highly conserved binding site in vesicle-associated membrane protein-associated protein (VAP) for the FFAT motif of lipid-binding proteins. J Biol Chem 280(14):14097-104
6) Byrne KP and Wolfe KH  (2005) The Yeast Gene Order Browser: combining curated homology and syntenic context reveals gene fate in polyploid species. Genome Res 15(10):1456-61
7) Manford AG, et al.  (2012) ER-to-Plasma Membrane Tethering Proteins Regulate Cell Signaling and ER Morphology. Dev Cell 23(6):1129-40
8) Hosaka K, et al.  (1994) Cloning and characterization of the SCS1 gene required for the expression of genes in yeast phospholipid synthesis. J Biochem (Tokyo) 115(1):131-6
9) Loewen CJ, et al.  (2003) A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J 22(9):2025-35
10) Brickner JH and Walter P  (2004) Gene recruitment of the activated INO1 locus to the nuclear membrane. PLoS Biol 2(11):e342
11) Loewen CJ, et al.  (2004) Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid. Science 304(5677):1644-7
12) Chen M, et al.  (2007) Transcriptional regulation of yeast phospholipid biosynthetic genes. Biochim Biophys Acta 1771(3):310-21
13) Cuperus G and Shore D  (2002) Restoration of silencing in Saccharomyces cerevisiae by tethering of a novel Sir2-interacting protein, Esc8. Genetics 162(2):633-45
14) Gerst JE  (1999) SNAREs and SNARE regulators in membrane fusion and exocytosis. Cell Mol Life Sci 55(5):707-34
15) Nishimura Y, et al.  (1999) Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins. Biochem Biophys Res Commun 254(1):21-6
16) Wyles JP and Ridgway ND  (2004) VAMP-associated protein-A regulates partitioning of oxysterol-binding protein-related protein-9 between the endoplasmic reticulum and Golgi apparatus. Exp Cell Res 297(2):533-47
17) Kaiser SE, et al.  (2005) Structural basis of FFAT motif-mediated ER targeting. Structure 13(7):1035-45
18) Nishimura AL, et al.  (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75(5):822-31