Genomes and Genes
Gene Symbol: KAR2
Description: Hsp70 family ATPase KAR2
Alias: GRP78, Hsp70 family ATPase KAR2
Species: Saccharomyces cerevisiae S288c
- Tyson J, Stirling C. LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. EMBO J. 2000;19:6440-52 pubmed..The Sil1 protein appears widespread amongst eukaryotes, with homologues in Yarrowia lipolytica (Sls1p), Drosophila and mammals. ..
- Matlack K, Misselwitz B, Plath K, Rapoport T. BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane. Cell. 1999;97:553-64 pubmed..Antibodies against the substrate can replace BiP, indicating that a Brownian ratchet is sufficient to achieve translocation. ..
- Brodsky J, Goeckeler J, Schekman R. BiP and Sec63p are required for both co- and posttranslational protein translocation into the yeast endoplasmic reticulum. Proc Natl Acad Sci U S A. 1995;92:9643-6 pubmed..of these proteins in cotranslational translocation, we examined the import of invertase into wild-type, sec63, and kar2 mutant yeast membranes...
- Mehnert M, Sommer T, Jarosch E. Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nat Cell Biol. 2014;16:77-86 pubmed publisher..Our data imply that Der1 initiates the export of aberrant polypeptides from the ER lumen by threading such molecules into the ER membrane and routing them to Hrd1 for ubiquitylation. ..
- Kimata Y, Oikawa D, Shimizu Y, Ishiwata Kimata Y, Kohno K. A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J Cell Biol. 2004;167:445-56 pubmed..We conclude that in the ER stress-sensory system BiP is not the principal determinant of Ire1 activity, but an adjustor for sensitivity to various stresses. ..
- Rose M, Misra L, Vogel J. KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene. Cell. 1989;57:1211-21 pubmed..The predicted KAR2 protein sequence is most homologous to mammalian BiP/GRP78 and has several structural features in common with it: a functional secretory signal sequence, a yeast endoplasmic ..
- Wang S, Ng D. Evasion of endoplasmic reticulum surveillance makes Wsc1p an obligate substrate of Golgi quality control. Mol Biol Cell. 2010;21:1153-65 pubmed publisher..By evading ERAD through these passive and active mechanisms, Wsc1p is fully dependent on the post-ER system for its quality control. ..
- Plemper R, Bordallo J, Deak P, Taxis C, Hitt R, Wolf D. Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. J Cell Sci. 1999;112 ( Pt 22):4123-34 pubmed..The retro-translocon seems to be build up at least by the Sec61 pore, Der3p/Hrd1p and Hrd3p and mediates both retrograde transport and ubiquitination of substrate molecules. ..
- Carla Famá M, Raden D, Zacchi N, Lemos D, Robinson A, Silberstein S. The Saccharomyces cerevisiae YFR041C/ERJ5 gene encoding a type I membrane protein with a J domain is required to preserve the folding capacity of the endoplasmic reticulum. Biochim Biophys Acta. 2007;1773:232-42 pubmed..We identified synthetic interactions of Deltaerj5 with mutations in genes involved in protein folding in the ER (kar2-159, Deltascj1Deltajem1) and in the induction of the unfolded protein response (Deltaire1)...
- Kabani M, Beckerich J, Gaillardin C. Sls1p stimulates Sec63p-mediated activation of Kar2p in a conformation-dependent manner in the yeast endoplasmic reticulum. Mol Cell Biol. 2000;20:6923-34 pubmed..Synthetic lethality was observed between DeltaScsls1 and translocation-deficient kar2 or sec63-1 mutants, providing in vivo evidence for a role of ScSls1p in protein translocation...
- Tokunaga M, Kawamura A, Kohno K. Purification and characterization of BiP/Kar2 protein from Saccharomyces cerevisiae. J Biol Chem. 1992;267:17553-9 pubmedUsing specific anti-BiP/Kar2 antibody as the probe, we have developed an efficient purification method of BiP/Kar2 protein from the total cell extract of Saccharomyces cerevisiae...
- Kimata Y, Kimata Y, Shimizu Y, Abe H, Farcasanu I, Takeuchi M, et al. Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell. 2003;14:2559-69 pubmed..kinase/ribonuclease Ire1, which causes the transcriptional induction of ER-resident chaperones, including BiP/Kar2. It was previously hypothesized that BiP/Kar2 plays a direct role in the signaling mechanism...
- Brizzio V, Khalfan W, Huddler D, Beh C, Andersen S, Latterich M, et al. Genetic interactions between KAR7/SEC71, KAR8/JEM1, KAR5, and KAR2 during nuclear fusion in Saccharomyces cerevisiae. Mol Biol Cell. 1999;10:609-26 pubmed..Overexpression of KAR8/JEM1 (but not SEC63) strongly suppressed the mating defect of kar2-1, suggesting that Kar2p interacts with Kar8/Jem1p for nuclear fusion...
- Hamilton T, Flynn G. Cer1p, a novel Hsp70-related protein required for posttranslational endoplasmic reticulum translocation in yeast. J Biol Chem. 1996;271:30610-3 pubmed..A strain possessing a null mutation of CER1 in combination with a kar2 temperature-sensitive mutation displays synthetic growth defects, whereas overexpression of the ER DnaJ homolog ..
- Nishikawa S, Fewell S, Kato Y, Brodsky J, Endo T. Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J Cell Biol. 2001;153:1061-70 pubmed..These results suggest that one role of the BiP, Jem1p, and Scj1p chaperones is to maintain lumenal ERAD substrates in a retrotranslocation-competent state. ..
- Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K. Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast. Biochem Biophys Res Commun. 2000;279:445-50 pubmed..Subsequently, KAR2 mRNA is induced and Kar2p accumulates in the ER in a time-dependent manner, restoring the system to the basal state...
- Schlenstedt G, Harris S, Risse B, Lill R, Silver P. 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. 1995;129:979-88 pubmed..These results indicate that the choice of an Hsp70 partner by a given DnaJ homologue is specified by the J domain. ..
- Yan M, Li J, Sha B. Structural analysis of the Sil1-Bip complex reveals the mechanism for Sil1 to function as a nucleotide-exchange factor. Biochem J. 2011;438:447-55 pubmed publisher..Mutation of the Sil1 residues involved in binding the Bip ATPase domain compromise the binding affinity of Sil1 to Bip, and these Sil1 mutants also abolish the ability to stimulate the ATPase activity of Bip. ..
- Denic V, Quan E, Weissman J. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell. 2006;126:349-59 pubmed
- Steel G, Fullerton D, Tyson J, Stirling C. Coordinated activation of Hsp70 chaperones. Science. 2004;303:98-101 pubmed..The two ATPase activities are coupled, and their coordinated regulation is essential for normal function in vivo. ..
- Corsi A, Schekman R. The lumenal domain of Sec63p stimulates the ATPase activity of BiP and mediates BiP recruitment to the translocon in Saccharomyces cerevisiae. J Cell Biol. 1997;137:1483-93 pubmed
- McClellan A, Endres J, Vogel J, Palazzi D, Rose M, Brodsky J. Specific molecular chaperone interactions and an ATP-dependent conformational change are required during posttranslational protein translocation into the yeast ER. Mol Biol Cell. 1998;9:3533-45 pubmed..We conclude that a conformation- and ATP-dependent interaction of BiP with the J domain of Sec63p is essential for protein translocation and that the specificity of hsc70 action is dictated by their DnaJ partners. ..
- Baxter B, James P, Evans T, Craig E. SSI1 encodes a novel Hsp70 of the Saccharomyces cerevisiae endoplasmic reticulum. Mol Cell Biol. 1996;16:6444-56 pubmed..The SSI1 promoter contains an element with similarity to the unfolded protein response element of KAR2. Like KAR2, SSI1 is induced both in the presence of tunicamycin and in a kar2-159 mutant strain, conditions which ..
- Oikawa D, Kimata Y. Experimental approaches for elucidation of stress-sensing mechanisms of the IRE1 family proteins. Methods Enzymol. 2011;490:195-216 pubmed publisher..Since this ability of yeast Ire1 was abolished by a mutation impairing its cellular activity, we propose that yeast Ire1 is fully activated by its direct interaction with unfolded proteins. ..
- Hrizo S, Gusarova V, Habiel D, Goeckeler J, Fisher E, Brodsky J. The Hsp110 molecular chaperone stabilizes apolipoprotein B from endoplasmic reticulum-associated degradation (ERAD). J Biol Chem. 2007;282:32665-75 pubmed..This study indicates that chaperones within distinct complexes can play unique roles during ER-associated degradation (ERAD), establishes a role for Sse1/Hsp110 in ERAD, and identifies Hsp110 as a target to lower cholesterol. ..
- MÃ©szÃ¡ros N, Cibulka J, Mendiburo M, Romanauska A, Schneider M, KÃ¶hler A. Nuclear pore basket proteins are tethered to the nuclear envelope and can regulate membrane curvature. Dev Cell. 2015;33:285-98 pubmed publisher..Basket amphipathic helices are functionally linked to distinct transmembrane nucleoporins of the NPC core, suggesting a key contribution to the membrane remodeling events that underlie NPC assembly. ..
- Wittke S, Dünnwald M, Albertsen M, Johnsson N. Recognition of a subset of signal sequences by Ssh1p, a Sec61p-related protein in the membrane of endoplasmic reticulum of yeast Saccharomyces cerevisiae. Mol Biol Cell. 2002;13:2223-32 pubmed
- Xu C, Wang S, Thibault G, Ng D. Futile protein folding cycles in the ER are terminated by the unfolded protein O-mannosylation pathway. Science. 2013;340:978-81 pubmed publisher..incapacitated target molecule folding and removed them from folding cycles by reducing engagement with the Kar2 chaperone...
- Todd Corlett A, Jones E, Seghers C, Gething M. Lobe IB of the ATPase domain of Kar2p/BiP interacts with Ire1p to negatively regulate the unfolded protein response in Saccharomyces cerevisiae. J Mol Biol. 2007;367:770-87 pubmed..Binding of an unfolded polypeptide to the substrate-binding domain of Kar2p could alter the positioning of glutamine 88 and other residues on lobe IB involved in binding Ire1p, releasing Ire1p for activation of UPR signaling. ..
- ..Genomic analysis of HSR targets reveals that >25% have function in common with UPR targets. We propose that HSR can relieve stress in UPR-deficient cells by affecting multiple ER activities. ..
- Zacchi L, Wu H, Bell S, Millen L, Paton A, Paton J, et al. The BiP molecular chaperone plays multiple roles during the biogenesis of torsinA, an AAA+ ATPase associated with the neurological disease early-onset torsion dystonia. J Biol Chem. 2014;289:12727-47 pubmed publisher..Together, these data define BiP as the first identified torsinA chaperone, and treatments that modulate BiP might improve symptoms associated with EOTD. ..
- te Heesen S, Aebi M. The genetic interaction of kar2 and wbp1 mutations. Distinct functions of binding protein BiP and N-linked glycosylation in the processing pathway of secreted proteins in Saccharomyces cerevisiae. Eur J Biochem. 1994;222:631-7 pubmed..In Saccharomyces cerevisiae, BiP is encoded by the KAR2 gene; WBP1 encodes an essential component of the N-oligosaccharyltransferase complex...
- Simons J, Ebersold M, Helenius A. Cell wall 1,6-beta-glucan synthesis in Saccharomyces cerevisiae depends on ER glucosidases I and II, and the molecular chaperone BiP/Kar2p. EMBO J. 1998;17:396-405 pubmed..We concluded that glucose trimming in S.cerevisiae is necessary for proper cell wall synthesis, and that the glucosidases function synergistically with BiP/Kar2p in this process. ..
- Wang J, Pareja K, Kaiser C, Sevier C. Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress. elife. 2014;3:e03496 pubmed publisher..We propose that alteration of BiP activity upon oxidation helps cells cope with disruption to oxidative folding within the ER during oxidative stress. ..
- Ng W, Sergeyenko T, Zeng N, Brown J, Römisch K. Characterization of the proteasome interaction with the Sec61 channel in the endoplasmic reticulum. J Cell Sci. 2007;120:682-91 pubmed..Mutations in the ATP-binding sites of individual Rpt proteins all reduced the affinity of 19S complexes for the ER, suggesting that the 19S base in the ATP-bound conformation docks at the Sec61 channel. ..
- Kimura T, Hosoda Y, Sato Y, Kitamura Y, Ikeda T, Horibe T, et al. Interactions among yeast protein-disulfide isomerase proteins and endoplasmic reticulum chaperone proteins influence their activities. J Biol Chem. 2005;280:31438-41 pubmed..Interestingly, co-chaperone activities were completely suppressed in Eps1p-Pdi1p and Eps1p-Mpd1p complexes, although only Eps1p and Pdi1p have chaperone activity. The in vivo consequences of these results are discussed. ..
- Ponsero A, Igbaria A, Darch M, Miled S, Outten C, Winther J, et al. Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip. Mol Cell. 2017;67:962-973.e5 pubmed publisher..enters the ER by facilitated diffusion through the Sec61 protein-conducting channel, while oxidized Bip (Kar2) inhibits transport...
- Zhang H, Hu B, Ji Y, Kato A, Song Y. The effect of calnexin deletion on the expression level of binding protein (BiP) under heat stress conditions in Saccharomyces cerevisiae. Cell Mol Biol Lett. 2008;13:621-31 pubmed publisher..It is suggested that under heat stress conditions, the induction of BiP in the ER might recover part of the function of calnexin in calnexin-disrupted yeast, and result in the same growth rate as in wild-type yeast. ..
- Takeuchi M, Kimata Y, Hirata A, Oka M, Kohno K. Saccharomyces cerevisiae Rot1p is an ER-localized membrane protein that may function with BiP/Kar2p in protein folding. J Biochem. 2006;139:597-605 pubmed..ROT1 genetically interacted with several ER chaperone genes including KAR2, and the rot1-2 mutation triggered the unfolded protein response...
- Marcinowski M, Höller M, Feige M, Baerend D, Lamb D, Buchner J. Substrate discrimination of the chaperone BiP by autonomous and cochaperone-regulated conformational transitions. Nat Struct Mol Biol. 2011;18:150-8 pubmed publisher..A major BiP cochaperone in antibody folding, ERdj3, modulated the conformational space of BiP in a nucleotide-dependent manner, placing the lid subdomain in an open, protein-accepting state. ..
- Kanehara K, Xie W, Ng D. Modularity of the Hrd1 ERAD complex underlies its diverse client range. J Cell Biol. 2010;188:707-16 pubmed publisher..The Hrd1 system does not directly evaluate the folding state of polypeptides. Instead, it does so indirectly, by recognizing specific embedded signals displayed upon misfolding. ..
- Andréasson C, Rampelt H, Fiaux J, Druffel Augustin S, Bukau B. The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp110. J Biol Chem. 2010;285:12445-53 pubmed publisher..As previously reported for Sse1, Lhs1 requires ATP to trigger nucleotide exchange in its cognate Hsp70 partner Kar2. Using site-specific cross-linking, we show that the nucleotide-binding domain (NBD) of Lhs1 interacts with the NBD ..
- Puts C, Lenoir G, Krijgsveld J, Williamson P, Holthuis J. A P4-ATPase protein interaction network reveals a link between aminophospholipid transport and phosphoinositide metabolism. J Proteome Res. 2010;9:833-42 pubmed publisher..Together, these findings suggest that aminophospholipid transport and phosphoinositide metabolism are interconnected at the Golgi. ..
- Wang J, Sevier C. Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress. J Biol Chem. 2016;291:7541-57 pubmed publisher..We propose the susceptibility of BiP to modification with glutathione may serve also to prevent irreversible oxidation of BiP by peroxide. ..
- Uchimura S, Sugiyama M, Nikawa J. Effects of N-glycosylation and inositol on the ER stress response in yeast Saccharomyces cerevisiae. Biosci Biotechnol Biochem. 2005;69:1274-80 pubmed..These results indicate that inositol, according to the numbers of glucose residues in the oligosaccharide, plays an important role in the stress response and quality control of glycoproteins in the ER. ..
- Hale S, Lovell S, de Keyzer J, Stirling C. Interactions between Kar2p and its nucleotide exchange factors Sil1p and Lhs1p are mechanistically distinct. J Biol Chem. 2010;285:21600-6 pubmed publisher..Taken together, these results demonstrate that the interactions between Kar2p and its two nucleotide exchange factors can be functionally resolved and are thus mechanistically distinct. ..
- Phan V, Ding V, Li F, Chalkley R, Burlingame A, McCormick F. The RasGAP proteins Ira2 and neurofibromin are negatively regulated by Gpb1 in yeast and ETEA in humans. Mol Cell Biol. 2010;30:2264-79 pubmed publisher..These findings provide evidence for conserved ubiquitination pathways regulating the RasGAP proteins Ira2 (in yeast) and neurofibromin (in humans). ..
- Kabani M, Beckerich J, Brodsky J. Nucleotide exchange factor for the yeast Hsp70 molecular chaperone Ssa1p. Mol Cell Biol. 2002;22:4677-89 pubmed..In support of this hypothesis, Fes1p was found to be associated with ribosomes. ..
- Lajoie P, Moir R, Willis I, Snapp E. Kar2p availability defines distinct forms of endoplasmic reticulum stress in living cells. Mol Biol Cell. 2012;23:955-64 pubmed publisher..Here we describe chromosomal tagging of KAR2, the yeast homologue of BiP, with superfolder green fluorescent protein (sfGFP) to create a multifunctional ..
- Suyama K, Hori M, Gomi K, Shintani T. Fusion of an intact secretory protein permits a misfolded protein to exit from the endoplasmic reticulum in yeast. Biosci Biotechnol Biochem. 2014;78:49-59 pubmed publisher..CPY*-Inv relied primarily on the p24 complex, a putative ER export receptor for invertase, for escape from ERAD, suggesting that the ERAD and the ER export of soluble secretory proteins are competitive. ..
- Markov D, Savkina M, Anikin M, Del Campo M, Ecker K, Lambowitz A, et al. Identification of proteins associated with the yeast mitochondrial RNA polymerase by tandem affinity purification. Yeast. 2009;26:423-40 pubmed publisher..Further, we found that Mss116p inhibits transcription by mtRNAP in vitro in a steady-state reaction. Our results support the hypothesis that Mss116p and Pet127p are involved in modulation of mtRNAP activity. ..
- Makio T, Nishikawa S, Nakayama T, Nagai H, Endo T. Identification and characterization of a Jem1p ortholog of Candida albicans: dissection of Jem1p functions in karyogamy and protein quality control in Saccharomyces cerevisiae. Genes Cells. 2008;13:1015-26 pubmed publisher..Since the interaction of CaJem1p with Nep98p is weaker than that of ScJem1p, the Nep98p-ScJem1p interaction is likely important for promoting karyogamy in S. cerevisiae. ..
- Copic A, DORRINGTON M, Pagant S, Barry J, Lee M, Singh I, et al. Genomewide analysis reveals novel pathways affecting endoplasmic reticulum homeostasis, protein modification and quality control. Genetics. 2009;182:757-69 pubmed publisher..Finally, the variant histone, Htz1p, and its acetylation state seem to play an important role in maintaining ER retrieval pathways, suggesting a surprising link between chromatin remodeling and ER homeostasis. ..
- Shin S, Bae Y, Kim S, Seong Y, Choi S, Kim K, et al. Effects of signal sequences and folding accessory proteins on extracellular expression of carboxypeptidase Y in recombinant Saccharomyces cerevisiae. Bioprocess Biosyst Eng. 2014;37:1065-71 pubmed publisher..7 times higher than that of the control strain. This work showed that engineering of signal sequences and protein-folding proteins would be helpful to overexpress yeast proteins of interest. ..
- Umebayashi K, Hirata A, Horiuchi H, Ohta A, Takagi M. Unfolded protein response-induced BiP/Kar2p production protects cell growth against accumulation of misfolded protein aggregates in the yeast endoplasmic reticulum. Eur J Cell Biol. 1999;78:726-38 pubmed..Instead, the growth was restored when an extra copy of the KAR2 gene, which encodes yeast BiP, was introduced, indicating that an increase in the amount of BiP is essential for ..
- Takeuchi M, Kimata Y, Kohno K. Saccharomyces cerevisiae Rot1 is an essential molecular chaperone in the endoplasmic reticulum. Mol Biol Cell. 2008;19:3514-25 pubmed publisher..In addition, their dependency on Rot1 appeared different. We therefore propose that Rot1 is a general chaperone with some substrate specificity. ..
- Xu M, Marsh H, Sevier C. A Conserved Cysteine within the ATPase Domain of the Endoplasmic Reticulum Chaperone BiP is Necessary for a Complete Complement of BiP Activities. J Mol Biol. 2016;428:4168-4184 pubmed publisher..We have shown previously that a cysteine within the ATPase domain of yeast BiP (Kar2) serves as a sensor of the endoplasmic reticulum (ER) redox environment [1, 2]...
- Ishiwata Kimata Y, Promlek T, Kohno K, Kimata Y. BiP-bound and nonclustered mode of Ire1 evokes a weak but sustained unfolded protein response. Genes Cells. 2013;18:288-301 pubmed publisher..We thus propose that upon persistent ER stress, Ire1 is weakly and continuously activated in a nonclustered form through its (re)association with BiP, which disperses the Ire1 clusters. ..
- Hsu C, Prasad R, Blackman C, Ng D. Endoplasmic reticulum stress regulation of the Kar2p/BiP chaperone alleviates proteotoxicity via dual degradation pathways. Mol Biol Cell. 2012;23:630-41 pubmed publisher..Despite hundreds of target genes under UPR control, we show that activation of KAR2 is indispensable to alleviate some forms of ER stress...