KAR2/YJL034W Summary Help

Standard Name KAR2
Systematic Name YJL034W
Alias GRP78
Feature Type ORF, Verified
Description ATPase involved in protein import into the ER, also acts as a chaperone to mediate protein folding in the ER and may play a role in ER export of soluble proteins; regulates the unfolded protein response via interaction with Ire1p (1, 2, 3 and see Summary Paragraph)
Name Description KARyogamy
Gene Product Alias BIP
Chromosomal Location
ChrX:381327 to 383375 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All KAR2 GO evidence and references
  View Computational GO annotations for KAR2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Mutant phenotypes All KAR2 Phenotype evidence and references
Classical genetics
null
reduction of function
Large-scale survey
null
overexpression
reduction of function
Resources
interactions All KAR2 Interaction evidence and references
549 total interaction(s) for 439 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 60
  • Affinity Capture-RNA: 3
  • Affinity Capture-Western: 28
  • Biochemical Activity: 2
  • Co-crystal Structure: 1
  • Co-fractionation: 1
  • Co-purification: 1
  • PCA: 3
  • Reconstituted Complex: 9
  • Two-hybrid: 40
Genetic Interactions
  • Dosage Lethality: 1
  • Dosage Rescue: 3
  • Negative Genetic: 40
  • Phenotypic Enhancement: 1
  • Phenotypic Suppression: 1
  • Positive Genetic: 335
  • Synthetic Growth Defect: 3
  • Synthetic Lethality: 15
  • Synthetic Rescue: 2
Resources
Expression Summary
histogram
Resources
Protein Information All KAR2 Protein evidence and references
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrX:381327 to 383375 | 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..2049 381327..383375 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 SGDIDS000003571
SUMMARY PARAGRAPH for KAR2

KAR2 encodes an essential protein that is a member of the HSP70 family of molecular chaperones (4, 5). In the lumen of the endoplasmic reticulum (ER), Kar2p binds to secretory and transmembrane precursor proteins to prevent their misfolding (5, 4). Kar2p also facilitates protein translocation into the ER (6), membrane fusion during karyogamy (4), and ER-associated degradation (7). Kar2p is a homolog of bacterial DnaK (8) and the mammalian protein BiP/GRP78/HSPA5 (OMIM) and has 67% identity to mouse BiP (4).

KAR2 has a high basal expression level which is further induced under conditions that lead to the accumulation of unfolded proteins and triggering of the Unfolded Protein Response (UPR) (4, 5). Not only is KAR2 expression induced by UPR, but Kar2p is also involved in regulating UPR through its interaction with the kinase/nuclease Ire1p (9). In the absence of unfolded peptides, Kar2p binds to Ire1p, maintaining Ire1p in an inactive state. During UPR, binding of an increased number of unfolded proteins to Kar2p causes the displacement of Kar2p from Ire1p (9, 3). Ire1p then adopts an active conformation, initiating a signal cascade that subsequently increases levels of the transcriptional activator Hac1p (reviewed in 10). Hac1p recognizes a 22 base pair UPR element, containing the consensus sequence 5'-CANCNTG-3', that is present in the promoters of UPR-regulated genes including KAR2 (11, 12). KAR2 expression is also induced by heat shock, a response separate from its response to unfolded protein stress and mediated by a heat shock element in the KAR2 promoter (5, 13).

Studies in homologous HSP70 proteins suggest that Kar2p substrate binding and release may be regulated by ATP (reviewed in 14). In S. cerevisiae, it has been shown that maximal Kar2p activity requires interaction with other proteins that stimulate ATP turnover. The intrinsically weak ATPase activity of Kar2p is enhanced by interaction with the DnaJ/HSP40 protein chaperone family members Sec63p, Scj1p, and Jem1p (8, 15, 16). Subsequent ADP-ATP exchange is promoted by the nucleotide exchange factor Sil1p and the protein chaperone Lhs1p (17, 18). It was also shown that the ATPase activity of Lhs1p is reciprocally activated by Kar2p (18).

Last updated: 2006-02-01

References cited on this page View Complete Literature Guide for KAR2
1) Romisch K  (1999) Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane. J Cell Sci 112 ( Pt 23)():4185-91
2) Tokunaga M, et al.  (1992) Purification and characterization of BiP/Kar2 protein from Saccharomyces cerevisiae. J Biol Chem 267(25):17553-9
3) Okamura K, et al.  (2000) Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast. Biochem Biophys Res Commun 279(2):445-50
4) Normington K, et al.  (1989) S. cerevisiae encodes an essential protein homologous in sequence and function to mammalian BiP. Cell 57(7):1223-36
5) Rose MD, et al.  (1989) KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene. Cell 57(7):1211-21
6) Matlack KE, et al.  (1999) BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane. Cell 97(5):553-64
7) Nishikawa SI, et al.  (2001) Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J Cell Biol 153(5):1061-70
8) Scidmore MA, et al.  (1993) Genetic interactions between KAR2 and SEC63, encoding eukaryotic homologues of DnaK and DnaJ in the endoplasmic reticulum. Mol Biol Cell 4(11):1145-59
9) Kimata Y, et al.  (2003) Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell 14(6):2559-69
10) Kaufman RJ  (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13(10):1211-33
11) Mori K, et al.  (1992) A 22 bp cis-acting element is necessary and sufficient for the induction of the yeast KAR2 (BiP) gene by unfolded proteins. EMBO J 11(7):2583-93
12) Mori K, et al.  (1998) Palindrome with spacer of one nucleotide is characteristic of the cis-acting unfolded protein response element in Saccharomyces cerevisiae. J Biol Chem 273(16):9912-20
13) Kohno K, et al.  (1993) The promoter region of the yeast KAR2 (BiP) gene contains a regulatory domain that responds to the presence of unfolded proteins in the endoplasmic reticulum. Mol Cell Biol 13(2):877-90
14) Bukau B and Horwich AL  (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92(3):351-66
15) Schlenstedt G, et al.  (1995) A yeast DnaJ homologue, Scj1p, can function in the endoplasmic reticulum with BiP/Kar2p via a conserved domain that specifies interactions with Hsp70s. J Cell Biol 129(4):979-88
16) Brizzio V, et al.  (1999) Genetic interactions between KAR7/SEC71, KAR8/JEM1, KAR5, and KAR2 during nuclear fusion in Saccharomyces cerevisiae. Mol Biol Cell 10(3):609-26
17) Kabani M, et al.  (2000) Sls1p stimulates Sec63p-mediated activation of Kar2p in a conformation-dependent manner in the yeast endoplasmic reticulum. Mol Cell Biol 20(18):6923-34
18) Steel GJ, et al.  (2004) Coordinated activation of Hsp70 chaperones. Science 303(5654):98-101