Limits...
A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1.

Kimata Y, Oikawa D, Shimizu Y, Ishiwata-Kimata Y, Kohno K - J. Cell Biol. (2004)

Bottom Line: Phenotypic comparison of several Ire1 mutants carrying deletions in the indispensable subregions suggests these subregions are responsible for multiple events that are prerequisites for activation of the overall Ire1 proteins.Unexpectedly, deletion of the BiP-binding site rendered Ire1 unaltered in ER stress inducibility, but hypersensitive to ethanol and high temperature.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.

View Article: PubMed Central - PubMed

Affiliation: Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan. kimata@bs.naist.jp

ABSTRACT
In the unfolded protein response, the type I transmembrane protein Ire1 transmits an endoplasmic reticulum (ER) stress signal to the cytoplasm. We previously reported that under nonstressed conditions, the ER chaperone BiP binds and represses Ire1. It is still unclear how this event contributes to the overall regulation of Ire1. The present Ire1 mutation study shows that the luminal domain possesses two subregions that seem indispensable for activity. The BiP-binding site was assigned not to these subregions, but to a region neighboring the transmembrane domain. Phenotypic comparison of several Ire1 mutants carrying deletions in the indispensable subregions suggests these subregions are responsible for multiple events that are prerequisites for activation of the overall Ire1 proteins. Unexpectedly, deletion of the BiP-binding site rendered Ire1 unaltered in ER stress inducibility, but hypersensitive to ethanol and high temperature. 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.

Show MeSH
Our current model to interpret structure and function of the yeast Ire1 luminal domain. Positions of conserved motifs deduced by interspecies sequence alignment of Ire1 and PERK (Liu et al., 2000), together with that of an unconserved sequence not present in Ire1 orthologues of higher eukaryotes (Liu et al., 2000, Koizumi et al., 2001) are indicated.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172501&req=5

fig9: Our current model to interpret structure and function of the yeast Ire1 luminal domain. Positions of conserved motifs deduced by interspecies sequence alignment of Ire1 and PERK (Liu et al., 2000), together with that of an unconserved sequence not present in Ire1 orthologues of higher eukaryotes (Liu et al., 2000, Koizumi et al., 2001) are indicated.

Mentions: This work was initiated from a serial and targeted mutagenesis study of the yeast IRE1 gene to understand the relationship of structure to function of the Ire1 luminal domain. As shown in Fig. 1 A and Fig. 2, the results predict that the yeast Ire1 luminal domain is divided into five subregions, among which subregions II and IV are indispensable for Ire1 activity. Liu et al. (2000) reported an interspecies comparison of Ire1 and PERK sequences, which predicted four conserved motifs (named Motif 1 to 4) in their luminal domains. As illustrated in Fig. 9, Motifs 1, 2, and 3 reside in subregion II, and Motif 4 in subregion IV. The interspecies comparison of Ire1 also shows that subregion I is carried only by yeast Ire1, as the sequences corresponding to subregion II neighbor the NH2-terminal translocation signal in metazoan and plant Ire1 orthologues (Liu et al., 2000; Koizumi et al., 2001). It seems that these findings provide a good example of the dogma that an evolutionarily conserved sequence is functionally important and vice versa.


A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1.

Kimata Y, Oikawa D, Shimizu Y, Ishiwata-Kimata Y, Kohno K - J. Cell Biol. (2004)

Our current model to interpret structure and function of the yeast Ire1 luminal domain. Positions of conserved motifs deduced by interspecies sequence alignment of Ire1 and PERK (Liu et al., 2000), together with that of an unconserved sequence not present in Ire1 orthologues of higher eukaryotes (Liu et al., 2000, Koizumi et al., 2001) are indicated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172501&req=5

fig9: Our current model to interpret structure and function of the yeast Ire1 luminal domain. Positions of conserved motifs deduced by interspecies sequence alignment of Ire1 and PERK (Liu et al., 2000), together with that of an unconserved sequence not present in Ire1 orthologues of higher eukaryotes (Liu et al., 2000, Koizumi et al., 2001) are indicated.
Mentions: This work was initiated from a serial and targeted mutagenesis study of the yeast IRE1 gene to understand the relationship of structure to function of the Ire1 luminal domain. As shown in Fig. 1 A and Fig. 2, the results predict that the yeast Ire1 luminal domain is divided into five subregions, among which subregions II and IV are indispensable for Ire1 activity. Liu et al. (2000) reported an interspecies comparison of Ire1 and PERK sequences, which predicted four conserved motifs (named Motif 1 to 4) in their luminal domains. As illustrated in Fig. 9, Motifs 1, 2, and 3 reside in subregion II, and Motif 4 in subregion IV. The interspecies comparison of Ire1 also shows that subregion I is carried only by yeast Ire1, as the sequences corresponding to subregion II neighbor the NH2-terminal translocation signal in metazoan and plant Ire1 orthologues (Liu et al., 2000; Koizumi et al., 2001). It seems that these findings provide a good example of the dogma that an evolutionarily conserved sequence is functionally important and vice versa.

Bottom Line: Phenotypic comparison of several Ire1 mutants carrying deletions in the indispensable subregions suggests these subregions are responsible for multiple events that are prerequisites for activation of the overall Ire1 proteins.Unexpectedly, deletion of the BiP-binding site rendered Ire1 unaltered in ER stress inducibility, but hypersensitive to ethanol and high temperature.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.

View Article: PubMed Central - PubMed

Affiliation: Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan. kimata@bs.naist.jp

ABSTRACT
In the unfolded protein response, the type I transmembrane protein Ire1 transmits an endoplasmic reticulum (ER) stress signal to the cytoplasm. We previously reported that under nonstressed conditions, the ER chaperone BiP binds and represses Ire1. It is still unclear how this event contributes to the overall regulation of Ire1. The present Ire1 mutation study shows that the luminal domain possesses two subregions that seem indispensable for activity. The BiP-binding site was assigned not to these subregions, but to a region neighboring the transmembrane domain. Phenotypic comparison of several Ire1 mutants carrying deletions in the indispensable subregions suggests these subregions are responsible for multiple events that are prerequisites for activation of the overall Ire1 proteins. Unexpectedly, deletion of the BiP-binding site rendered Ire1 unaltered in ER stress inducibility, but hypersensitive to ethanol and high temperature. 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.

Show MeSH